# 49 - 166 Diseases Caused by Gram-Negative Enteric Bacilli

### 166 Diseases Caused by Gram-Negative Enteric Bacilli

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■FURTHER READING
Craig R et al: Asymptomatic infection and transmission of pertussis in 
households: A systematic review. Clin Infect Dis 70:152, 2020.
Forsyth KD et al: Recommendations to control pertussis prioritized 
relative to economies: A Global Pertussis Initiative update. Vaccine 
36:7270, 2018.
Havers FP et al: Use of tetanus toxoid, reduced diphtheria toxoid, and 
acellular pertussis vaccines: Updated recommendations of the Advi­
sory Committee on Immunization Practices—United States, 2019. 
MMWR Morb Mortal Wkly Rep 69:77, 2020.
Ma L et al: Pertactin-deficient Bordetella pertussis, vaccine-driven evo­
lution, and reemergence of pertussis. Emerg Infect Dis 27:1561, 2021.
Macina D et al: Estimating the pertussis burden in adolescents and 
adults in the United States between 2007 and 2019. Hum Vaccin 
Immunother 19:2208514, 2023.
Miguelena Chamorro B et al: Bordetella bronchiseptica and Bordetella 
pertussis: Similarities and differences in infection, immuno-modula­
tion, and vaccine considerations. Clin Microbiol Rev 36:e0016422, 
2023.
Skoff TH: Sources of infant pertussis infection in the United States. 
Pediatrics 136:635, 2015.
Tatti KM et al: Novel multitarget real-time PCR assay for rapid detec­
tion of Bordetella species in clinical specimens. J Clin Microbiol 
49:4059, 2011.
Winter K et al: Pertussis in California: A tale of 2 epidemics. Pediatr 
Infect Dis J 37:324, 2018.
Wright J et al: Uptake of pertussis immunization in pregnancy and 
determinants of vaccination in Toronto, Canada. Vaccine 41: 6895, 
2023.
Thomas A. Russo, Yohei Doi

Diseases Caused by 

Gram-Negative Enteric 

Bacilli
GENERAL FEATURES AND PRINCIPLES
The postantibiotic era has begun. For most patients, this is the first time 
in their lives when an effective treatment for a bacterial infection may 
not exist. Species in the order Enterobacterales are at the forefront of 
this evolving public health crisis. For example, the Centers for Disease 
Control and Prevention (CDC) and the World Health Organization 
(WHO) have designated carbapenem-resistant Enterobacterales (CRE) 
as representing a threat level of “urgent” and “priority one, critical.” 
CRE are estimated to have caused more than 100,000 deaths in 2019 
globally, and the disease burden is especially high in low- and middleincome countries (e.g., Indian Subcontinent). These pathogens cause 
a wide variety of infections involving diverse anatomic sites, mostly in 
compromised hosts but also in healthy individuals. Therefore, a thor­
ough knowledge of clinical presentations and appropriate therapeutic 
choices is necessary for optimal outcomes. Escherichia coli, Klebsiella, 
Proteus, Enterobacter, Serratia, Citrobacter, Morganella, Providencia, 
Cronobacter, and Edwardsiella are enteric gram-negative bacilli (GNB) 
within the order Enterobacterales that commonly cause extraintestinal 
infections. Salmonella, Shigella, and Yersinia, which also are in the 
order Enterobacterales but more commonly cause gastrointestinal 
infections, are discussed in Chaps. 171, 172, and 176, respectively.
■
■EPIDEMIOLOGY
E. coli, Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, Morgan­
ella, Providencia, Cronobacter, and Edwardsiella are components of the 

normal animal and human colonic microbiota and/or the microbiota 
in various environmental habitats, including long-term-care facilities 
(LTCFs) and hospitals. As a result, except for certain pathotypes of 
intestinal pathogenic E. coli, these genera are global pathogens. The 
incidence of infection due to these agents is increasing because of the 
combination of an aging population and increasing antimicrobial resis­
tance. In healthy humans, E. coli is the predominant species of GNB 
in the colonic microbiota, followed by Klebsiella and Enterobacter. 
GNB can also colonize the oropharynx and intact skin but, in healthy 
individuals, tend to do so only transiently. By contrast, in LTCFs and 
hospital settings, a variety of GNB emerge as the dominant colonizers 
of both mucosal and skin epithelial surfaces, particularly in associa­
tion with antimicrobial use, severe illness, and extended length of stay. 
LTCFs are emerging as an important reservoir for resistant GNB. 
Such colonization with GNB may lead to subsequent extraintestinal 
infection; for example, oropharyngeal colonization may lead to pneu­
monia, and colonic/perineal colonization may lead to urinary tract 
infection (UTI). The use of ampicillin or amoxicillin was associated 
with an increased risk of subsequent infection due to the hypervirulent 
pathotype of Klebsiella pneumoniae in Taiwan; this association suggests 
that changes in the quantity or prevalence of colonizing bacteria may 
significantly influence the risk of infection. Serratia, Enterobacter, and, 
less commonly, Citrobacter infection may be acquired directly through 
a variety of contaminated infusates (e.g., medications, blood products, 
non–U.S. Food and Drug Administration [FDA]-approved stem cell 
products). A multistate outbreak of highly resistant Serratia due to con­
taminated eyedrops has occurred. Edwardsiella infections are acquired 
through freshwater and marine environment exposures and are most 
common in Southeast Asia.

CHAPTER 166
■
■STRUCTURE AND FUNCTION
Enteric GNB possess an extracytoplasmic outer membrane consisting 
of a lipid bilayer with associated proteins, lipoproteins, and polysac­
charides (capsule, lipopolysaccharide). The outer membrane interfaces 
with the external environment, including the human host. A variety of 
components of the outer membrane are critical determinants in patho­
genesis (e.g., capsule, lipopolysaccharide) and antimicrobial resistance 
(e.g., permeability barrier, efflux pumps). In addition, secreted prod­
ucts play an important role in both host infection (e.g., iron acquisition 
molecules) and environmental niche survival and colonization (e.g., 
type VI secretion systems).
Diseases Caused by Gram-Negative Enteric Bacilli  
■
■PATHOGENESIS
Multiple bacterial virulence factors are required for the pathogenesis 
of infections caused by GNB. Possession of specialized virulence genes 
defines pathogens and enables them to infect the host efficiently. Hosts 
and their cognate pathogens have been co-adapting throughout evo­
lutionary history. During the host–pathogen “chess match” over time, 
various and redundant strategies have emerged in both the pathogens 
and their hosts (Table 166-1).
Intestinal pathogenic (diarrheagenic) mechanisms are discussed 
below. The members of the order Enterobacterales that cause extrain­
testinal infections are primarily extracellular pathogens and therefore 
share certain pathogenic features. The two principal components of 
host defense against Enterobacterales, regardless of species, are innate 
immunity (including intact skin and mucosal barriers; the withholding 
of nutrients; and the activities of complement, antimicrobial peptides, 
and professional phagocytes) and humoral immunity. Both suscep­
tibility to and severity of infection are increased with dysfunction or 
deficiencies of these host components. By contrast, the virulence traits 
of intestinal pathogenic E. coli—i.e., the distinctive strains that can 
cause diarrheal disease—are for the most part different from those of 
extraintestinal pathogenic E. coli (ExPEC) and other GNB that cause 
extraintestinal infections. This distinction reflects site-specific dif­
ferences in host environments, defense mechanisms, and physiologic 
derangements that lead to disease.
A given enterobacterial strain usually possesses multiple adhesins 
for binding to a variety of host cells (e.g., in E. coli: type 1, S, and 
F1C fimbriae; P pili). Nutrient acquisition (e.g., of iron via

TABLE 166-1  Interactions of Extraintestinal Pathogenic Escherichia coli 
with the Human Host: A Paradigm for Extracellular, Extraintestinal, 
Gram-Negative Bacterial Pathogens
BACTERIAL GOAL
HOST OBSTACLE
BACTERIAL SOLUTION
Extraintestinal 
attachment
Flow of urine, mucociliary 
escalator
Multiple adhesins 
(e.g., type 1, S, and F1C 
fimbriae; P pili)
Nutrient acquisition for 
growth
Nutrient sequestration 
(e.g., iron via 
intracellular storage and 
extracellular scavenging 
via lactoferrin and 
transferrin)
Cellular lysis (e.g., 
hemolysin), multiple 
mechanisms for 
competing for iron (e.g., 
siderophores) and other 
nutrients
Initial avoidance of host 
bactericidal activity
Complement, phagocytic 
cells, antimicrobial 
peptides
Capsular polysaccharide, 
lipopolysaccharide
Dissemination (within 
host and between hosts)
Intact tissue barriers
Irritant tissue damage 
resulting in increased 
excretion (e.g., toxins 
such as hemolysin), 
invasion of brain 
endothelium
Late avoidance of host 
bactericidal activity
Acquired immunity (e.g., 
specific antibodies), 
treatment with antibiotics
Cell entry, acquisition of 
antimicrobial resistance
siderophores) requires many genes that are necessary but not sufficient 
for pathogenesis. The ability to resist the bactericidal activity of com­
plement and phagocytes in the absence of antibody (e.g., as conferred 
by capsule or the O antigen component of lipopolysaccharide) is one of 
the defining traits of an extracellular pathogen. Tissue damage (e.g., as 
mediated by E. coli hemolysin) may facilitate nutrient acquisition and 
spread within the host. Without doubt, many important virulence 
genes await identification.
PART 5
Infectious Diseases
The ability to induce septic shock is another defining feature of these 
genera. GNB are the most common causes of this potentially lethal 
syndrome. Pathogen-associated molecular pattern molecules (PAMPs; 
e.g., the lipid A moiety of lipopolysaccharide) stimulate a proinflam­
matory host response via pattern recognition receptors (e.g., Toll-like 
or C-type lectin receptors) that activate host defense signaling path­
ways; if overly exuberant, this response results in shock (Chap. 315). 
Direct bacterial damage of host tissue (e.g., by toxins) or collateral 
damage from the host response can result in the release of damageassociated molecular pattern molecules (DAMPs; e.g., HMGB1) that 
can propagate a detrimental proinflammatory host response.
Many antigenic variants (serotypes) exist in most genera of GNB. For 
example, E. coli has >150 O (somatic) antigens, 80 K (capsular) antigens, 
and 53 H (flagellar) antigens. This antigenic variability, which permits 
immune evasion and allows recurrent infection by different strains of 
the same species, has impeded vaccine development (Chap. 129).
■
■INFECTIOUS SYNDROMES
Depending on both the host and the pathogen, GNB can infect nearly 
every organ or body cavity. E. coli can cause either intestinal or extrain­
testinal infection, depending on the pathotype, and Edwardsiella tarda 
can cause both intestinal and extraintestinal infection. Klebsiella causes 
primarily extraintestinal infection, but a toxin-producing variant of 
Klebsiella oxytoca has been associated with hemorrhagic colitis, and 
Providencia alcalifaciens and Escherichia albertii have been associated 
with gastroenteritis.
E. coli and—to a lesser degree—Klebsiella account for most extrain­
testinal infections due to GNB. These species (for K. pneumoniae, 
primarily its hypervirulent pathotype) are the most virulent pathogens 
within this group, as demonstrated by their ability to cause severe 
infections in healthy, ambulatory hosts from the community. However, 
the other genera of GNB are also important extraintestinal pathogens, 
especially among LTCF residents and hospitalized patients, in large 
part because of the intrinsic or acquired antimicrobial resistance 
of these organisms and the increasing number of individuals with 

compromised host defenses. The mortality rate is substantial in many 
GNB infections and correlates with severity of illness, underlying host 
status, and in some cases the antimicrobial resistance of the infecting 
pathogen, which can result in suboptimal therapy. Especially problem­
atic are pneumonia, sepsis, and septic shock (arising from any site of 
infection), for which the associated mortality rates are 20–60%.
■
■DIAGNOSIS
Isolation of GNB from sterile sites almost always implies infection, 
whereas their isolation from nonsterile sites, particularly open wounds, 
the respiratory tract, and urine in the presence of an indwelling cath­
eter, requires careful clinical correlation to differentiate colonization 
from infection. Clinical microbiology laboratories are increasingly 
replacing identification by biochemical tests with newer diagnostic 
methodologies such as matrix-assisted laser desorption–ionization–
time-of-flight mass spectrometry (MALDI-TOF-MS), nucleic acid 
amplification tests (NAATs) and sequencing, and immunoassays to 
enhance the sensitivity, accuracy, and rapidity of reporting on patho­
gen identification and resistance genes. This information can be used 
to increase the timeliness of initiation and/or the accurate selection of 
empirical antimicrobial therapy, thereby improving outcomes. These 
new diagnostic modalities have also resulted in the identification from 
clinical specimens of unfamiliar species (e.g., K. grimontii, Enterobacter 
hormaechei). It is best to assume such isolates possess a similar patho­
genic potential as their more familiar counterparts until more data 
become available.
TREATMENT
Principles Guiding Treatment in the Era of 
Increasing Antimicrobial Resistance
(See also Chap. 149) Initiation of appropriate empirical anti­
microbial therapy early in the course of infections due to GNB 
(particularly the more serious ones) leads to improved outcomes. 
The ever-increasing prevalence of multidrug-resistant (MDR) and 
extensively drug-resistant (XDR) GNB; the lag between published 
and current resistance rates; and variations in antimicrobial suscep­
tibility by species, geographic location, regional antimicrobial use, 
and hospital site (e.g., intensive care units [ICUs] vs wards) neces­
sitate familiarity with evolving patterns of antimicrobial resistance 
for the selection of appropriate empirical therapy.
Patient factors predictive of resistance in a given isolate include 
recent antimicrobial use, a health care association (e.g., recent or 
ongoing hospitalization, dialysis, residence in an LTCF, transplant, 
hematologic malignancy), or international travel (e.g., to Asia, Latin 
America, Africa, Eastern Europe). Of concern are an increasing 
number of reports of resistant Enterobacterales causing infections 
in ambulatory patients without known risk factors.
In this era of increasing antimicrobial resistance, it is critical to 
culture the primary site of infection before initiating antimicrobial 
therapy and, for systemically ill patients, to obtain blood cultures. 
In vitro testing may not always detect antimicrobial resistance; 
therefore, it is important to assess the patient’s clinical response to 
treatment. Moreover (see discussion of AmpC β-lactamases below), 
resistance may emerge during therapy. In addition, drainage of 
abscesses, resection of necrotic tissue, and removal of infected for­
eign bodies, sometimes referred to collectively as “source control,” 
are often required for cure.
For appropriately selected patients, it may be prudent initially, 
pending antimicrobial susceptibility results, to use two potentially 
active agents to increase the likelihood that at least one agent 
will be active against the patient’s organism. If broad-spectrum 
treatment has been initiated, it is important to switch to the most 
appropriate narrower-spectrum agent once antimicrobial suscep­
tibility results become available. Such responsible antimicrobial 
stewardship should help disrupt the ever-escalating cycle of selec­
tion for increasingly resistant bacteria, plus decrease the likelihood 
of Clostridioides difficile infection, decrease costs, and maximize

the useful longevity of available antimicrobial agents. Likewise, it is 
important to avoid treatment of patients who are colonized but not 
infected (e.g., who have a positive sputum culture without evidence 
of pneumonia, or a positive urine culture without clinical manifes­
tations of UTI).
At present, the most reliably and broadly active antimicrobial 
agents in vitro against Enterobacterales are the carbapenems (except­
ing imipenem, to which Proteeae [Proteus, Morganella, Providencia] 
are intrinsically resistant); the aminoglycoside amikacin (excepting 
the Proteeae); the fourth-generation cephalosporin cefepime; the 
β-lactamase inhibitor combination agents piperacillin-tazobactam, 
ceftolozane-tazobactam, 
ceftazidime-avibactam, 
meropenemvaborbactam, and imipenem/cilastatin-relebactam; and the novel 
cephalosporin-siderophore cefiderocol. A limitation of imipenem/
cilastatin-relebactam; the tetracycline derivatives tigecycline, oma­
dacycline, and eravacycline; and the polymyxins B and E (colistin) 
(which are otherwise very active) is their poor activity against 

Proteeae and Serratia. Furthermore, the tetracycline derivatives 
achieve suboptimal concentrations at several anatomic sites 
(including urine and blood). Clinical data are limited for cefidero­
col outside of UTIs and hospital-acquired ventilator-associated 
bacterial pneumonias; thus, caution is in order for serious infec­
tions at other sites.
The number of antimicrobial agents active against certain strains 
of Enterobacterales is shrinking, and truly pandrug-resistant GNB 
exist. Accordingly, the currently available antimicrobial drugs must 
be used judiciously. Extensive resistance to available agents may leave 
the clinician with few or no ideal therapeutic options. However, use 
of a regimen that considers the site of infection, achievable drug levels 
at that site (e.g., higher concentrations of many agents in urine), and 
pharmacodynamically guided administration strategies (e.g., pro­
longed infusion of β-lactam agents to maintain drug levels above the 
minimal inhibitory concentration [MIC]) may increase the chance 
for a successful outcome. Point-of-care, NAAT-based identification 
of resistance mechanisms in GNB is becoming available and will 
enable a strain-specific, patient-specific, precision medicine–based 
treatment approach that would be predicted to improve outcome.
GNB are commonly involved in polymicrobial infections, in 
which the role of each individual pathogen is uncertain (Chap. 182). 
Although some GNB are more pathogenic than others, it is usu­
ally prudent, if possible, to design an antimicrobial regimen active 
against all the GNB identified, because each is typically capable of 
pathogenicity in its own right. For patients treated initially with 
a broad-spectrum empirical regimen, the regimen should be deescalated as expeditiously as possible once susceptibility results are 
known and the patient has responded to therapy.
Treatment duration is best individualized based on underlying 
host status and site of infection. However, for selected non–critically 
ill patients with source control and a satisfactory clinical response 
to therapy, 7 days of treatment may suffice for many infections. 
ANTIMICROBIAL TREATMENT AND RESISTANCE 
MECHANISMS
The most common resistance mechanisms possessed by Enterobac­
terales are summarized in Table 166-2. Enzymatic hydrolysis (e.g., 
β-lactamases, of which >3000 variants have been described) and 
modification of antimicrobials are the major mediators of resistance 
in GNB and will be discussed below. Importantly, it is becoming 
increasingly recognized that MDR and XDR GNB often possess 
multiple plasmids and genes that encode for multiple β-lactamases.
Broad-spectrum β-lactamases mediate resistance to many peni­
cillins and first-generation cephalosporins and are frequently 
expressed in enteric GNB. These enzymes are inhibited by all avail­
able β-lactamase inhibitors (e.g., clavulanate, sulbactam, tazobac­
tam, avibactam, relebactam, vaborbactam). In their wild-type form, 
they do not hydrolyze third- and fourth-generation cephalosporins 
or cephamycins (e.g., cefoxitin).
Extended-spectrum β-lactamases (ESBLs) are modified broadspectrum enzymes that hydrolyze third-generation cephalosporins, 

TABLE 166-2  Common Antimicrobial Resistance Mechanisms 
Possessed by the Enterobacterales
ANTIMICROBIALS 
MOST SIGNIFICANTLY 
AFFECTED
COMMON MEDIATORS 

OF RESISTANCE
MECHANISM
Efflux
Tetracyclines, 
fluoroquinolones (FQ)
Efflux pumps
Decreased 
permeability
Fosfomycin
Alterations in uptake system
Target site alteration 
or overproduction
FQ, trimethoprimsulfamethoxazole (TMPSMX), and polymyxins
DNA gyrase or topoisomerase 
IV for FQ; enzymes for folic 
acid synthesis for TMP-SMX
Lipid A for polymyxins
Enzymatic 
hydrolysis of 
antimicrobials
Penicillins, 
cephalosporins, 
cephamycins, 
carbapenems
Broad-spectrum β-lactamases 
(e.g., TEM, SHV)
ESBLs (e.g., CTX-M, modified 
TEM and SHV)
AmpC β-lactamases
Carbapenemases (e.g., serinebased KPC, OXA; metallobased NDM, VIM, IMP)
Enzymatic 
modification of 
antimicrobials
Aminoglycosides
AAC, ANT, APH
Abbreviations: AAC, N-acetyltransferases; ANT, O-adenylyltransferases; 
APH, O-phosphotransferases; CTX, cefotaxime β-lactamase; ESBL, extendedspectrum β-lactamase; IMP, active on imipenem; KPC, Klebsiella pneumoniae 
carbapenemase; NDM, New Delhi metallo-β-lactamase; OXA, oxacillinase; SHV, 
sulfhydryl reagent variable β-lactamase; TEM, Temoniera β-lactamase; VIM, Verona 
integron-mediated metallo-β-lactamase.
CHAPTER 166
aztreonam, and (in some instances) fourth-generation cephalo­
sporins, in addition to the drugs hydrolyzed by broad-spectrum 
β-lactamases. GNB that produce ESBLs may also exhibit porin 
mutations that result in decreased uptake of relevant β-lactam 
agents (cephalosporins, β-lactam/β-lactamase inhibitor combina­
tions, and carbapenems), further reducing susceptibility to these 
agents. The prevalence of acquired ESBL production, particularly 
of CTX-M-type enzymes, is increasing in GNB worldwide, largely 
due to the presence of the corresponding genes on transferable plas­
mids, which also variably confer or are associated with resistance 
to fluoroquinolones, trimethoprim-sulfamethoxazole (TMP-SMX), 
aminoglycosides, tetracyclines, and (more recently) fosfomycin. 
To date, ESBLs are most prevalent in E. coli (especially ST131), K. 
pneumoniae, and K. oxytoca, but these enzymes can occur in all 
species of Enterobacterales. The approximate regional prevalence of 
ESBL-producing GNB currently follows a descending gradient as 
follows: China > Eastern Europe > other parts of Asia (e.g., India) 
> Latin America and Africa > Western Europe, the United States, 
Canada, and Australia. Travel to high-prevalence regions increases 
the likelihood of colonization with these strains. The incidence of 
community-acquired infections due to ESBL-producing Entero­
bacterales has increased worldwide, including in the United States.
Diseases Caused by Gram-Negative Enteric Bacilli  
Carbapenems are the most reliably active β-lactam agents against 
ESBL-producing strains. Piperacillin-tazobactam, when active in 
vitro, has been used as a carbapenem-sparing alternative, but recent 
data from the MERINO trial do not support its use for bloodstream 
infections. Ceftazidime-avibactam, ceftolozane-tazobactam (less 
active against Klebsiella, Enterobacter, and Citrobacter) are also 
active against most ESBL-producing strains but have limited clinical 
data that support potential utility. The roles for tigecycline, eravacy­
cline, and omadacycline are unclear despite these agents’ excellent 
in vitro activity against most Enterobacterales; however, they are 
inactive against Proteus, Morganella, Providencia, and Serratia.
Oral options for the treatment of ESBL-producing strains are 
very limited. Fosfomycin, nitrofurantoin (for E. coli, 75–90% sus­
ceptible), pivmecillinam (recently approved in the United States), 
and omadacycline are the most reliably active agents. Older tetra­
cyclines (e.g., doxycycline and minocycline) also are often active,

although urine levels may be insufficient and clinical experience 
with gram-negative infections is limited.

AmpC β-lactamases, when induced or stably derepressed to high 
levels of expression, confer resistance to the same substrates as 
do ESBLs plus to the cephamycins (e.g., cefoxitin and cefotetan), 
except to the fourth-generation cephalosporins. The genes encod­
ing these enzymes are primarily chromosomal and therefore may 
not exhibit the linked resistance to TMP-SMX, aminoglycosides, 
and tetracyclines that is common with ESBLs. These enzymes 
are problematic for the clinician: resistance may develop dur­
ing therapy with third-generation cephalosporins and result in 
clinical failure, particularly in the setting of bacteremia. Although 
chromosomal AmpC β-lactamases are present in nearly all mem­
bers of the order Enterobacterales (with the notable exceptions of 

K. pneumoniae, K. oxytoca, and Proteus mirabilis), the risk of clinically 
significant induction of high-level expression or selection of stably 
derepressed mutants with cephalosporin treatment is not uniform 
across species, being greatest with Enterobacter cloacae, Klebsiella 
(formerly Enterobacter) aerogenes, Citrobacter freundii, and Hafnia 
alvei, and less with Serratia marcescens, Providencia, and Morganella 
morganii. In addition, rare strains of E. coli, K. pneumoniae, and 
other Enterobacterales have acquired plasmids that contain AmpC 
β-lactamase genes.
For AmpC-producing strains, carbapenems are an appropriate 
treatment option, especially for severely ill patients. Meta-analyses 
support piperacillin-tazobactam as a possible option. The fourthgeneration cephalosporin cefepime may be an appropriate option 
if the concomitant production of an ESBL can be excluded (a task 
that currently exceeds the capability of most clinical microbiol­
ogy laboratories) and source control is achieved. Ceftazidimeavibactam and cefiderocol are active in vitro, but clinical data 
are limited. Other carbapenem-sparing alternatives to consider if 
isolates are susceptible in vitro include fluoroquinolones, TMPSMX, and aminoglycosides. Tigecycline, eravacycline, and oma­
dacycline are active in vitro (except against Proteus, Morganella, 
Providencia, and Serratia).
PART 5
Infectious Diseases
Carbapenemases of Ambler class A (serine-β-lactamases; e.g., 
K. pneumoniae carbapenemase [KPC]) and class B (metallo-βlactamases [MBLs]; e.g., New Delhi metallo-β-lactamase [NDM], 
Verona integron-mediated metallo-β-lactamase [VIM], imipen­
emase [IMP]) confer resistance to the same drugs as do ESBLs, 
plus to cephamycins and carbapenems. By contrast, Ambler class 
D carbapenemases (serine-β-lactamases; e.g., oxacillinase-48 
[OXA-48]) hydrolyze carbapenems and penicillins, but they have 
minimal activity against extended-spectrum cephalosporins. As 
with ESBLs, carbapenemase-encoding genes may be present on 
transferable plasmids, which often encode linked resistance to 
fluoroquinolones, TMP-SMX, tetracyclines, and aminoglycosides. 
Transposon-mediated spread (e.g., Tn4401 for KPC) also is impor­
tant. Although all major carbapenemases have been described 
around the globe, KPC is most common in the Americas, NDM 
in Asia, and OXA in Europe. Asymptomatic intestinal carriage of 
producing bacteria may facilitate spread.
Carbapenemase-producing Enterobacterales (CPE) are most 
prevalent in K. pneumoniae, followed by Enterobacter spp. and 

E. coli, but have been described in nearly all members of the order. 
M. morganii, Proteus, and Providencia exhibit intrinsic low-level 
imipenem resistance. A variety of genotypic and phenotypic meth­
ods can detect carbapenemase genes or activity, which could inform 
epidemiologic surveillance, infection control efforts, antimicrobial 
stewardship, and treatment decisions, especially if susceptibility 
data for selected agents are not available.
For the treatment of infections due to Enterobacterales that 
produce class A or D carbapenemases (serine-β-lactamases; KPC, 
OXA), ceftazidime-avibactam is emerging as a first-line agent 
particularly for bacteremia, but suboptimal efficacy has been 
observed with pneumonia and in patients on renal replacement 
therapy, and resistance has developed in up to 10% of cases. Clini­
cal success against KPC-producing CRE has also been reported 

for meropenem-vaborbactam and, to a lesser extent, imipenem/
cilastatin-relebactam; unlike ceftazidime-avibactam, however, 
neither of these agents is active against OXA-producing CRE. 
Ceftazidime, cefepime, and aztreonam are active against OXA48-producing CRE, unless other enzymes such as ESBL an AmpC 
are co-produced.
Treatment of infections due to class B MBL–producing CRE is 
more challenging. The polymyxins B and E currently constitute one 
of the last lines of defense against strains that produce MBLs (e.g., 
NDM). However, these agents’ nephrotoxicity and neurotoxicity 
potential, their limited clinical efficacy, and the recent emergence 
of the polymyxin resistance threaten their utility.
Aztreonam is stable against MBLs but is hydrolyzed by ESBLs 
and AmpC β-lactamases, which are often coproduced in XDR 
strains. Ongoing clinical trials are assessing aztreonam plus avibac­
tam, a promising combination with in vitro activity against class A, 
B, and D enzymes, for the treatment of CRE strains that produce 
MBLs like NDM. A currently available workaround involving 
approved drugs is co-administration of ceftazidime-avibactam and 
aztreonam; avibactam protects aztreonam from hydrolysis from 
ESBLs and AmpC β-lactamases.
Cefiderocol is active in vitro against most strains producing 
KPC, MBLs, and OXA-48 (i.e., classes A, B, and D enzymes); 
clinical trials suggest that it may be as efficacious for serious CRE 
infections as the standard of care, but real-world data are limited. 
Although tigecycline, eravacycline, and omadacycline are active in 
vitro, pharmacokinetic-pharmacodynamic limitations exist, and 
along with the polymyxins, they exhibit poor activity against the 
tribe Proteeae and Serratia. Aminoglycosides, especially amikacin, 
may have some utility for combination therapy. Fosfomycin is 
often active in vitro, but clinical data in the treatment of serious 
infections due to CPE are limited and resistance may develop with 
monotherapy.
Carbapenem resistance in the absence of carbapenemases can 
occur in the presence of ESBLs or AmpC β-lactamase production in 
combination with porin mutations (non-CP-CRE); however, most 
laboratories will not be able to differentiate CPE from non-CP-CRE. 
The non-CP-CRE phenotype is most commonly seen in E. coli and 
Enterobacter spp. In general, resistance to noncarbapenem antimi­
crobial classes is less, but data are limited on the optimal manage­
ment approach for non-CP-CRE.
Resistance to classic β-Lactamase inhibitors is an uncommon (4% 
of E. coli/K. pneumoniae blood isolates) but increasingly recog­
nized phenotype that is characterized by resistance to β-lactamase 
inhibitors but not to third-generation cephalosporins. This mecha­
nism of resistance is distinct from production of ESBLs, AmpC 
β-lactamases, and carbapenemases, and it is still being delineated. 
Limited evidence suggests that ceftriaxone is an appropriate treat­
ment option for such strains. Resistance to newer β-lactamase 
inhibitors, especially avibactam, is increasingly reported in KPCproducing CPE and is due to mutations leading to structural modi­
fications of the KPC enzyme. These strains remain susceptible to 
meropenem-vaborbactam.
Fluoroquinolone resistance is usually due to alterations in or 
protection of the target sites in DNA gyrase and topoisomerase 
IV, with or without decreased permeability and active efflux. Fluo­
roquinolone resistance is increasingly prevalent among GNB and 
is associated with resistance to other antimicrobial classes; for 
example, 20–80% of ESBL-producing enteric GNB are also resis­
tant to fluoroquinolones. At present, fluoroquinolones should be 
considered unreliable as empirical therapy for GNB infections in 
critically ill patients.
Aminoglycoside resistance in Enterobacterales is conferred via 
enzymatic modification by N-acetyltransferases, O-adenylyltrans­
ferases, or O-phosphotransferases, which in turn affects ribosomal 
binding. Amikacin is less affected by these transferases than gen­
tamicin and tobramycin and therefore is generally more active. 
A yet uncommon resistance mechanism involves acquired 16S 
ribosomal RNA methyltransferases, which prevent all parenterally

administered aminoglycosides from binding to their target ribo­
somes. To date, these methyltransferases are most common in 
strains that produce MBLs (e.g., NDM).
■
■PREVENTION
(See also Chap. 147) Certain measures are broadly applicable for 
decreasing infection risk. Antimicrobial stewardship programs should 
be instituted to facilitate appropriate antimicrobial use, which will 
minimize the development of resistance. Diligent adherence to hand 
hygiene protocols by health care personnel and cleaning/disinfection 
or single-patient use of objects that come into contact with patients 
(e.g., stethoscopes and blood pressure cuffs) are essential. Indwelling 
devices (e.g., urinary and intravascular catheters) should be used only 
when necessary and inserted according to an appropriate protocol; 
protocols for daily-use evaluation and prompt removal should be 
implemented. Multiuse medication vials should be avoided if possible. 
Oral application of chlorhexidine decreases the incidence of pneumo­
nia among patients on ventilators. Increasing data support the imple­
mentation of universal decolonization (e.g., chlorhexidine bathing) 
to prevent infection in ICU patients or nursing home residents. The 
public health threat from CRE has resulted in additional recommen­
dations, especially for carbapenemase-producing CRE, which are an 
even greater concern. These recommendations include contact precau­
tions for patients colonized or infected with CRE, notification to the 
receiving facility from facilities transferring such a patient, and daily 
environmental cleaning. Screening of contacts and active surveillance 
for these bacteria also may be appropriate.
ESCHERICHIA COLI INFECTIONS
All E. coli strains share a core genome of ~2,000 genes. In con­
trast, an E. coli strain’s ability to cause infection and the nature of 
such infections are defined largely by accessory (i.e., noncore, 
nonessential) genes that encode various virulence factors. The compo­
sition of the E. coli accessory genome is continuously in flux, as dem­
onstrated by the recent evolution of Shiga toxin–producing 
enteroaggregative E. coli.
■
■COMMENSAL STRAINS
Commensal E. coli variants are an important constituent of the normal 
intestinal microbiota that confer benefits to the host (e.g., resistance 
to colonization with pathogenic organisms). Such strains generally 
lack the specialized virulence traits that enable extraintestinal and 
intestinal pathogenic E. coli strains to cause disease outside and within 
the gastrointestinal tract, respectively. However, even commensal 

E. coli strains can be involved in extraintestinal infections in the pres­
ence of an aggravating factor, such as a foreign body (e.g., a urinary 
catheter), host compromise (e.g., local anatomic or functional abnor­
malities [including urinary or biliary tract obstruction] or systemic 
TABLE 166-3  Intestinal Pathogenic Escherichia coli
PATHOTYPE
EPIDEMIOLOGY
CLINICAL SYNDROMEa
DEFINING MOLECULAR TRAIT
STEC/EHEC/
ST-EAEC
Food, water, person-to-person; all ages, 
industrialized countries
Hemorrhagic colitis, hemolyticuremic syndrome
ETEC
Food, water; young children in and 
travelers to developing countries
Traveler’s diarrhea
Heat-stable and labile enterotoxins, 
colonization factors
EPEC
Person-to-person; young children and 
neonates in developing countries
Watery diarrhea, persistent 
diarrhea
EIEC
Food, water; children in and travelers to 
developing countries
Watery diarrhea, occasionally 
dysentery
EAEC
?Food, water; children in and travelers 
to developing countries; all ages, 
industrialized countries
Traveler’s diarrhea, acute 
diarrhea, persistent diarrhea
aClassic syndromes; see text for details on disease spectrum. bPathogenesis involves multiple genes, including genes in addition to those listed.
Abbreviations: EAEC, enteroaggregative E. coli; EHEC, enterohemorrhagic E. coli; EIEC, enteroinvasive E. coli; EPEC, enteropathogenic E. coli; ETEC, enterotoxigenic E. coli; 
ST-EAEC, Shiga toxin–producing enteroaggregative E. coli; STEC, Shiga toxin–producing E. coli.

immunocompromise), or an inoculum that is large or contains a 
mixture of bacterial species (e.g., fecal contamination of the peritoneal 
cavity).

■
■EXTRAINTESTINAL PATHOGENIC STRAINS
ExPEC strains are the most common enteric GNB to cause communityacquired and health care–associated bacterial infections. The emerging 
propensity of these strains to acquire new mechanisms of antimicrobial 
resistance (e.g., FQ resistance mutations, ESBLs, carbapenemases) 
poses novel challenges in managing ExPEC infection. Several ExPEC 
clonal groups (e.g., sequence types [STs] ST131, ST95, ST69, ST73) 
are recognized to have undergone global dissemination. The mecha­
nisms underlying the epidemiologic success of such disseminated 
lineages remain an area of active investigation. In the case of ST131, 
efficient human-to-human transmission followed by colonization and 
long-term persistence within the intestinal microbiota appears to be 
a critical factor. Although acquisition of ESBL-producing E. coli from 
the food chain has been described, this appears to occur relatively 
uncommonly.
Like commensal E. coli (but unlike intestinal pathogenic E. coli), 
ExPEC strains are often found in the intestinal microbiota of healthy 
individuals and, except for rare chimeric ExPEC/intestinal pathogenic 
E. coli strains, do not cause gastroenteritis in humans. Entry from 
their site of colonization (e.g., the colon, vagina, or oropharynx) into 
a normally sterile extraintestinal site (e.g., the urinary tract, peritoneal 
cavity, or lungs) is the rate-limiting step for infection. ExPEC strains 
have acquired accessory genes encoding diverse virulence factors that 
enable the bacteria to cause infections outside the gastrointestinal tract 
in both normal and compromised hosts (Table 166-1). These virulence 
genes define ExPEC and, for the most part, are distinct from the viru­
lence genes that enable intestinal pathogenic strains to cause diarrheal 
disease (Table 166-3). All age groups, all types of hosts, and nearly all 
organs and anatomic sites are susceptible to infection by ExPEC. Even 
previously healthy hosts can become severely ill or die when infected 
with ExPEC; however, adverse outcomes are more common among 
hosts with comorbid illnesses and host defense abnormalities. The 
diversity and the medical and economic impact of ExPEC infections 
are evident from consideration of the following specific syndromes.
CHAPTER 166
Diseases Caused by Gram-Negative Enteric Bacilli  
Extraintestinal Infectious Syndromes  •  URINARY TRACT 
INFECTION 
The urinary tract is the site most frequently infected by 
ExPEC. UTI is an exceedingly common infection among ambulatory 
patients, accounting for 1% of ambulatory care visits in the United States 
and second only to lower respiratory tract infection among infections 
responsible for hospitalization. UTIs are best considered by clinical 
syndrome (e.g., cystitis, pyelonephritis, catheter-associated UTI) and 
within the context of specific hosts (e.g., premenopausal women, 
immunocompromised hosts; Chap. 140). E. coli is the single most 
common pathogen for all UTI syndrome/host group combinations. 
RESPONSIBLE GENETIC 
ELEMENTb
Shiga toxin
Lambda-like Stx1- or Stx2encoding bacteriophage
Virulence plasmid(s)
Localized adherence, attaching and 
effacing lesion on intestinal epithelium
EPEC adherence factor plasmid 
pathogenicity island (locus for 
enterocyte effacement [LEE])
Invasion of colonic epithelial cells, 
intracellular multiplication, cell-to-cell 
spread
Multiple genes contained primarily 
in a large virulence plasmid
Aggregative/diffuse adherence, 
virulence factors regulated by AggR
Chromosomal or plasmidassociated adherence and toxin 
genes

Each year in the United States, E. coli causes 80–90% of the estimated 
6–8 million episodes of cystitis that occur in ambulatory, premeno­
pausal women with an anatomically and functionally normal urinary 
tract (i.e., uncomplicated cystitis). Furthermore, 20% of women with 
an initial cystitis episode develop frequent recurrences.

Uncomplicated cystitis, the most common acute UTI syndrome, is 
characterized by dysuria, urinary frequency and urgency, and supra­
pubic pain. Progression to more severe infection is rare; the natural 
history is slow spontaneous symptom resolution, which antimicrobial 
therapy hastens. Fever and/or back pain suggest progression to pyelo­
nephritis. Even when pyelonephritis is treated effectively, fever may 
take 5–7 days to resolve completely. Persistently elevated or increasing 
fever, flank pain, and neutrophil counts should prompt evaluation for 
intrarenal or perinephric abscess and/or obstruction. Pyelonephritis 
uncommonly causes renal parenchymal damage and loss of renal func­
tion, primarily in association with urinary obstruction, which can be 
preexisting or, rarely, occurs de novo in diabetic patients who develop 
renal papillary necrosis due to kidney infection. Pregnant women are at 
unusually high risk for developing pyelonephritis, which can adversely 
affect the outcome of pregnancy. As a result, prenatal screening for and 
treatment of asymptomatic bacteriuria during pregnancy are standard. 
Prostatic infection (prostatitis), a potential complication of UTI in 
men, can present either acutely (severe), which is rare, or in a chronic 
manner (recurrent cystitis), which is much more common. Acute 
pyelonephritis, acute prostatitis, and other systemic illnesses due to 
UTI can be designated collectively as urosepsis, febrile UTI, or systemic 
UTI, and may or may not be accompanied by bacteremia. The diagno­
sis and treatment of UTI, as detailed in Chap. 140, should be tailored to 
the individual host, the nature and site of infection, and local patterns 
of antimicrobial susceptibility.
PART 5
Infectious Diseases
ABDOMINAL AND PELVIC INFECTION  The abdomen/pelvis is the 
second most common site of extraintestinal infection due to E. coli. 
A wide variety of clinical syndromes occur in this location, includ­
ing acute peritonitis secondary to fecal contamination, spontane­
ous bacterial peritonitis, dialysis-associated peritonitis, diverticulitis, 
appendicitis, intraperitoneal or visceral abscesses (hepatic, pancreatic, 
splenic), infected pancreatic pseudocysts, and septic cholangitis and/or 
cholecystitis. In intraabdominal infections, E. coli can be isolated either 
alone or, as occurs more often, in combination with other facultative 
and/or anaerobic members of the intestinal microbiota (Chap. 137).
PNEUMONIA  E. coli is not usually considered an important cause of 
pneumonia (Chap. 131). Indeed, enteric GNB account for only 1–3% 
of cases of community-acquired pneumonia, in part because these 
organisms colonize the oropharynx only transiently in a minority of 
healthy individuals. However, rates of oral colonization with E. coli 
and other GNB increase with severity of illness and antibiotic use. 
Consequently, GNB are a more common cause of pneumonia among 
residents of LTCFs and of hospital-acquired pneumonia (Chap. 147), 
particularly among postoperative and ICU patients (e.g., ventilatorassociated pneumonia).
Pulmonary infection is usually acquired by small-volume aspira­
tion but occasionally occurs via hematogenous spread, in which case 
multifocal nodular infiltrates can be seen. Tissue necrosis, probably 
due in part to bacterial cytotoxins, is common. Despite significant 
institutional variation, E. coli is generally the third or fourth most 
commonly isolated type of GNB in hospital-acquired pneumonia, 
accounting for 5–8% of episodes in both U.S.-based and Europe-based 
studies. Regardless of the host, pneumonia due to ExPEC is a serious 
disease, with high crude and attributable mortality rates (20–60% and 
10–20%, respectively).
MENINGITIS  (See also Chap. 143) E. coli is one of the leading causes 
of neonatal meningitis, together with group B Streptococcus. Most E. 
coli strains that cause neonatal meningitis possess the K1 capsular 
antigen and derive from a limited number of meningitis-associated 
clonal groups (ST95, ST59, ST62). Ventriculomegaly occurs com­
monly. After the first month of life, E. coli meningitis is uncommon and 
usually accompanies surgical or traumatic disruption of the meninges 
or hepatic cirrhosis. In patients with cirrhosis who develop meningitis, 

the meninges are presumably seeded due to poor hepatic clearance of 
portal vein bacteremia.
CELLULITIS/MUSCULOSKELETAL INFECTION  E. coli contributes fre­
quently to infections of decubitus ulcers and occasionally to infections 
of lower-extremity ulcers and wounds in diabetic patients and other 
hosts with neurovascular compromise. Osteomyelitis secondary to 
contiguous spread can occur in these settings. E. coli also causes cel­
lulitis or infections of burn sites and surgical wounds (accounting for 
~10% of surgical site infections), particularly when the infection origi­
nates close to the perineum. E. coli causes hematogenously acquired 
osteomyelitis, especially of vertebral discs and bodies, accounting for 
up to 10% of cases in some series (Chap. 136). E. coli occasionally 
causes orthopedic device–associated infection or septic arthritis and 
rarely causes hematogenous myositis. Myositis or fasciitis of the thigh 
due to E. coli should prompt an evaluation for an abdominal source 
with contiguous spread.
ENDOVASCULAR INFECTION  Despite being one of the most common 
causes of bacteremia, E. coli rarely seeds native heart valves. When the 
organism does infect native valves, it usually does so in the setting of 
prior valvular disease. E. coli infections of aneurysms, the portal vein 
(pylephlebitis), and vascular grafts are uncommon.
MISCELLANEOUS INFECTIONS  E. coli can cause infection in nearly 
every organ and anatomic site. It occasionally causes postoperative 
mediastinitis or complicated sinusitis and uncommonly causes endo­
phthalmitis, ecthyma gangrenosum, or brain abscess.
BACTEREMIA  E. coli bacteremia can arise from infection at any extrain­
testinal site. In addition, E. coli bacteremia can arise from percutaneous 
intravascular devices, transrectal prostate biopsy, and the increased intes­
tinal mucosal permeability seen in neonates and patients with advanced 
cirrhosis, neutropenia, chemotherapy-induced mucositis, trauma, and 
extensive burns. E. coli bacteremia due to an ESBL-producing strain 
also has been reported after fecal microbiota transplant in patients with 
increased mucosal permeability. Roughly equal proportions of E. coli 
bacteremia cases originate in the community and in health care settings. 
Isolation of E. coli from the blood is almost always clinically significant 
and may be accompanied by the sepsis syndrome (dysfunction of at least 
one organ or system) or septic shock (Chap. 315).
The urinary tract is the most common source for E. coli bacteremia, 
accounting for one-half to two-thirds of episodes. Bacteremia from 
a urinary tract source is particularly common among patients with 
pyelonephritis, urinary tract obstruction, or urinary instrumentation 
in the presence of infected urine. The abdomen is the second most 
common source, accounting for ~25% of episodes. Although many 
of these episodes result from biliary obstruction (stones, tumor) and 
overt bowel disruption, which typically are readily apparent, some 
abdominal sources (e.g., abscesses) are remarkably silent clinically and 
require identification via imaging studies (e.g., computed tomogra­
phy). Therefore, especially given the high prevalence of asymptomatic 
bacteriuria among elderly and functionally compromised individuals, 
the physician should be cautious in attributing E. coli bacteremia to a 
urinary source in the absence of characteristic signs and symptoms of 
UTI. Soft tissue, bone, pulmonary infections, and intravascular cath­
eter infections are other sources of E. coli bacteremia.
Diagnosis 
Strains of E. coli that cause extraintestinal infections usu­
ally grow both aerobically and anaerobically within 24 h on standard 
diagnostic media and are identified readily by the clinical microbiology 
laboratory according to routine biochemical criteria. More than 90% 
of ExPEC strains are rapid lactose fermenters and are indole-positive. 
However, MALDI-TOF MS is increasingly replacing biochemical 
methods.
TREATMENT
Extraintestinal E. coli Infections
E. coli does not possess clinically significant intrinsic resistance 
to antimicrobials; however, increasing acquired resistance is

making treatment problematic. Although geographic differences 
exist, in general, the prevalence of resistance is >20% for ampi­
cillin, amoxicillin-clavulanate, ampicillin-sulbactam, cefazolin, 
TMP-SMX, and fluoroquinolones, even in community-acquired 
infections. This resistance precludes empirical use of these agents 
for serious infections. Travel outside of the United States, prior 
exposure to an antimicrobial agent, or exposure to a health care 
setting further increases the likelihood of resistance. Fortunately, 
>90% of isolates that cause uncomplicated cystitis remain suscep­
tible to nitrofurantoin and fosfomycin.
From 2015 to 2017, the U.S. National Healthcare Safety Network 
(USNHSN) identified 24% of E. coli clinical isolates as ESBLproducers. Higher prevalences are reported from Asia, Eastern 
Europe, South America, and Africa; prevalence is also greater in 
isolates from health care settings, especially LTCFs. Unfortunately, 
community-acquired UTIs caused by E. coli strains that produce 
CTX-M ESBLs are increasingly common. Oral treatment options 
for ESBL-producers are limited. However, in vitro and limited clini­
cal data indicate that fosfomycin, pivmecillinam, and nitrofurantoin 
are most active and can be used for cystitis (but not pyelonephritis); 
omadacycline is an option for pulmonary of soft-tissue infection.
For parenteral therapy of carbapenem-susceptible strains, the 
most predictably active agents (>90%) include carbapenems, ami­
kacin, ceftazidime-avibactam, ceftolozane-tazobactam, piperacillintazobactam, polymyxins, cefiderocol, tigecycline, eravacycline, and 
omadacycline with the caveat that site-specific concentration and 
potential efficacy are agent dependent. Treatment of carbapenemaseproducing strains is dependent on the class of enzyme produced 
(see “Carbapenemase” above). Uncertainty exists on the optimal 
treatment for non-CP-CR E. coli.
Empirical treatment decisions for critically ill patients should be 
dictated by local susceptibility patterns and patient-specific risk fac­
tors (1.2% prevalence from the USNHSN 2015−2017 data). Equally 
important as prompt institution of effective empirical therapy for 
seriously ill patients is use of appropriate narrower-spectrum agents 
for definitive therapy whenever possible and avoidance of treatment 
for patients who are colonized but not infected.
■
■INTESTINAL PATHOGENIC STRAINS
Pathotypes 
Certain strains of E. coli are capable of causing diar­
rheal disease. (Other important intestinal pathogens are discussed 
in Chaps. 138, 139, and 171–174.) At least in the industrialized 
world, intestinal pathogenic E. coli strains are rarely encountered in 
the fecal flora of healthy persons, and instead appear to be essentially 
obligate pathogens. These strains have evolved a special ability to 
cause enteritis, enterocolitis, and colitis when ingested in sufficient 
quantities by a naïve host. At least five distinct pathotypes of intestinal 
pathogenic E. coli exist: (1) Shiga toxin–producing E. coli (STEC), 
which includes the subsets enterohemorrhagic E. coli (EHEC) and the 
recently evolved Shiga toxin–producing enteroaggregative E. coli (STEAEC); (2) enterotoxigenic E. coli (ETEC); (3) enteropathogenic E. coli 
(EPEC); (4) enteroinvasive E. coli (EIEC); and (5) enteroaggregative 

E. coli (EAEC). Diffusely adherent E. coli (DAEC) and cytodetach­
ing E. coli are additional putative pathotypes. Lastly, a variant termed 
adherent invasive E. coli (AIEC) has been associated with Crohn disease 
(although a causal role remains unproven) but does not cause acute 
diarrheal disease.
Contaminated food and water are the primary transmission vehicles 
for ETEC, STEC/EHEC/ST-EAEC, EIEC, and EAEC, whereas personto-person spread (direct or indirect) is the primary transmission 
route for EPEC and a secondary transmission route for STEC/EHEC/
ST-EAEC. Gastric acidity confers some protection against infection; 
therefore, persons with decreased stomach acid levels are especially 
susceptible. Humans are the major reservoir for such strains (except 
for STEC/EHEC, for which bovines are the main carriers); host range 
appears to be dictated by species-specific attachment factors. Although 
some overlap exists, each pathotype possesses a distinctive combina­
tion of virulence traits that results in a pathotype-specific pathogenic 

mechanism (Table 166-3). With rare exceptions (e.g. DAEC), these 
strains are largely incapable of causing disease outside the intestinal 
tract. Whereas disease due to STEC/EHEC/ST-EAEC occurs primar­
ily in high-income countries, disease due to ETEC, EPEC, and EIEC 
occurs primarily in low- and middle-income countries in Asia, Africa, 
and Latin America, and disease due to EAEC occurs globally.

SHIGA TOXIN–PRODUCING E. COLI  STEC/EHEC/ST-EAEC strains 
are pathogens that can cause hemorrhagic colitis and the hemolyticuremic syndrome (HUS). In contrast to other intestinal pathotypes, 
STEC/EHEC/ST-EAEC causes infections more frequently in highincome countries than in low and middle-income countries (LMICs). 
Several large outbreaks resulting from the consumption of fresh 
produce (e.g., lettuce, spinach, sprouts) and of undercooked ground 
beef have received significant media attention. In addition, a dramatic 
2011 outbreak—mainly in Germany—involved an EAEC strain that 
acquired a Shiga toxin–encoding phage, resulting in a novel genotype, 
ST-EAEC (O104:H4). This strain was transmitted to the primary cases 
by sprouted fenugreek seeds, with subsequent human-to-human trans­
mission, and resulted in >4000 cases and 54 deaths.
STEC strains are the fourth most commonly reported cause of bac­
terial diarrhea in the United States (after Campylobacter, Salmonella, 
and Shigella). O157:H7 is the most prominent serotype among STEC 
strains, but many other serogroups have been described, including O6, 
O26, O45, O55, O91, O103, O111, O113, O121, and O145. Domesti­
cated ruminant animals, particularly cattle and young calves, serve as 
the major reservoir for STEC/EHEC. Ground or mechanically tender­
ized beef—the most common food source of STEC/EHEC strains—is 
often contaminated with intestinal bacteria from the source ani­
mals during processing. Furthermore, manure from cattle or other 
animals (including in the form of fertilizer) can contaminate produce 
(potatoes, lettuce, spinach, sprouts, fallen fruits, nuts, strawberries), 
and fecal runoff from manure can contaminate water systems. Dairy 
products and petting zoos are additional sources of infection.
CHAPTER 166
Diseases Caused by Gram-Negative Enteric Bacilli  
It is estimated that <102 colony-forming units (CFU) of STEC/
EHEC/ST-EAEC can cause disease. Therefore, not only can low levels 
of food or environmental contamination (e.g., in water swallowed 
while swimming) result in disease, but person-to-person transmission 
(e.g., at day-care centers and in institutions) is an important route for 
secondary spread. Laboratory-associated infections also occur. Illness due 
to this group of pathogens peaks in the summer months and occurs 
both as outbreaks and as sporadic cases.
For STEC/EHEC/ST-EAEC, production of Shiga toxin (Stx2a–g 
and/or Stx1a,c,d) is a critical factor for occurrence of clinical dis­
ease, as demonstrated by the 2011 ST-EAEC outbreak. The stx 
gene is present on chromosomally integrated prophages, and various 
combinations of stx types and subtypes can occur in a given strain. 
Shigella dysenteriae strains that produce the closely related Shiga toxin 
Stx can also cause hemorrhagic colitis and HUS. Stx2 (especially 
Stx2a,c,d) appears to be more important than Stx1 in the development 
of HUS. All Shiga toxins studied to date are multimers; they comprise 
one A subunit that is enzymatically active and five identical B subunits 
that mediate binding to globosyl ceramides, which are membraneassociated glycolipids expressed on certain host cells. As in ricin, the 
Stx A subunit cleaves an adenine from the host cell’s 28S rRNA, thereby 
irreversibly inhibiting ribosomal function (i.e., protein synthesis) and 
potentially leading to apoptosis.
For full pathogenicity, STEC strains require additional properties 
such as acid tolerance and epithelial cell adherence. Most disease-caus­
ing isolates possess the chromosomal locus for enterocyte effacement 
(LEE). This pathogenicity island was first described in EPEC strains; it 
contains genes that mediate adherence to intestinal epithelial cells and 
a system that subverts host cells by the translocation of bacterial pro­
teins (type III secretion system). EHEC strains make up the subgroup 
of STEC strains that possess stx1 and/or stx2, as well as LEE. By con­
trast, the 2011 ST-EAEC outbreak strain lacked LEE yet was associated 
with a higher proportion of patients developing HUS (22%) than the 
historic average for STEC/EHEC outbreaks (2–8%). Data support the 
essential role of the 2011 outbreak strain’s EAEC-associated virulence

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

After exposure to STEC/EHEC/ST-EAEC and a 3- to 4-day incuba­
tion period, colonization of the colon and perhaps the ileum results in 
symptoms. Colonic edema and an initial nonbloody secretory diarrhea 
may progress to the hallmark syndrome of grossly bloody diarrhea (iden­
tified by history or examination). Significant abdominal pain and fecal 
leukocytes are common (70% of cases), whereas fever is not; absence of 
fever can incorrectly lead to consideration of noninfectious conditions 
(e.g., intussusception and inflammatory or ischemic bowel disease). 
Occasionally, infections caused by C. difficile, K. oxytoca (see “Klebsiella 
Infections,” below), Campylobacter, and Salmonella present in a similar 
fashion. STEC/EHEC disease is usually self-limited, lasting 5–10 days.
A feared complication of infection with STEC/EHEC strains is HUS, 
which occurs 2–14 days after diarrhea, most often in young children 
(estimated to occur in 15% of infected children <10 years of age) or 
elderly patients. It is estimated that in the United States >50% of all 
HUS cases—and 90% of HUS cases in children, which is a leading 
cause of acute renal failure in this latter population—are caused by 
STEC/EHEC. By contrast, with ST-EAEC infection, HUS occurs more 
commonly among nonelderly adults, especially young women. HUS is 
mediated by the systemic translocation of Shiga toxins. Erythrocytes 
may serve as carriers of Stx to endothelial cells located in the small 
vessels of the kidney and brain. The subsequent development of throm­
botic microangiopathy (perhaps with direct toxin-mediated effects on 
various nonendothelial cells) commonly produces some combination 
of fever, hemolytic anemia (hematocrit <30%), thrombocytopenia 
(<150,000/mm3), renal failure, and encephalopathy. Stx-mediated 
complement activation also plays a role in the development of HUS. 
Although with dialysis support the mortality rate of HUS is <10%, sur­
vivors often have persisting renal and neurologic dysfunction.
PART 5
Infectious Diseases
ENTEROTOXIGENIC E. COLI  ETEC is a major cause of endemic diar­
rhea in low- and middle-income countries and is responsible for an 
estimated 800 million cases annually. After weaning, children in these 
locales commonly experience several episodes of ETEC infection dur­
ing the first 3 years of life. The incidence of disease diminishes with 
age, a pattern that correlates with the development of mucosal immu­
nity to colonization factors (i.e., adhesins).
In industrialized countries, ETEC is the most common agent of 
traveler’s diarrhea, causing 25–75% of cases. The incidence of infection 
may be decreased by prudent avoidance of potentially contaminated 
fluids and foods, particularly items that are raw, insufficiently cooked, 
peeled, or unrefrigerated (Chap. 130). ETEC infection is uncommon 
in the United States, but outbreaks secondary to consumption of 
food products imported from endemic areas have occurred. A large 
inoculum (106–108 CFU) is needed to produce disease, which usually 
develops after an incubation period of 12–72 h.
 After adherence of ETEC to enterocytes via colonization factors 
(e.g., CFA/I, CS), disease is mediated, primarily by a heat-labile 
toxin (LT) and/or a heat-stable toxin (ST), leading to diarrheal 
disease. Disease is less severe with strains that produce only LT. Both 
LT and ST cause net fluid secretion via activation of adenylate cyclase 
and/or guanylate cyclase C (ST) in the jejunum and ileum. The result 
is watery diarrhea accompanied by cramps.
LT consists of an A and a pentameric B subunit and is structur­
ally and functionally similar to cholera toxin. Strong binding of the 
B subunit to the GM1 ganglioside on intestinal epithelial cells leads to 
the intracellular translocation of the A subunit, which functions as an 
ADP-ribosyltransferase. Mature ST is an 18- or 19-amino-acid secreted 
peptide that leads to increased intracellular concentrations of cGMP. 
Characteristically absent in ETEC-mediated disease are histopatho­
logic changes within the small bowel; mucus, blood, and inflammatory 
cells in stool; and fever.
The disease spectrum of ETEC infection ranges from mild illness to 
a life-threatening, cholera-like syndrome. Although symptoms are usu­
ally self-limited (typically lasting for 3–5 days), infection may result in 
significant morbidity and mortality (>250,000 deaths annually, mostly 

from profound volume depletion) when access to health care or suit­
able rehydration fluids is limited and when small and/or undernour­
ished children are affected.
ENTEROPATHOGENIC E. COLI  EPEC causes disease primarily in young 
children, including neonates. The first E. coli pathotype recognized 
as an agent of diarrheal disease, EPEC was responsible for outbreaks 
of infantile diarrhea (including in hospital nurseries) in industrial­
ized countries in the 1940s and 1950s. At present, EPEC infection is 
uncommon in high-income countries, but among infants in low- and 
middle-income countries, it is an important cause of diarrhea (both 
sporadic and epidemic), often accompanied by vomiting and fever. 
Breast-feeding diminishes the incidence of EPEC infection. Rapid 
person-to-person spread may occur.
Symptoms develop after colonization of the small bowel and a 
brief incubation period (1 or 2 days). Initial localized adherence 
to enterocytes via type IV bundle-forming pili leads to a charac­
teristic effacement of microvilli, with the formation of cuplike, actinrich pedestals mediated by factors in the LEE. Diarrhea production is a 
complex and regulated process in which host cell modulation by a type III 
secretion system plays an important role. Strains lacking bundleforming pili have been categorized as atypical EPEC (aEPEC); increas­
ing data support a role for these strains as intestinal pathogens in all age 
groups and among HIV-infected individuals. Diarrheal stool often 
contains mucus but not blood. Although EPEC diarrhea is usually selflimited (lasting 5–15 days), it may persist for weeks.
ENTEROINVASIVE E. COLI  EIEC, a relatively uncommon (or per­
haps underrecognized) cause of diarrhea, is rarely identified in 
the United States, although a few food-related outbreaks have been 
described. In low- and middle-income countries, sporadic disease is 
recognized infrequently in children and travelers.
EIEC shares many genetic and clinical features, as well as a common 
ancestor, with Shigella. Both are intracellular pathogens for which viru­
lence is mediated by the presence of specific factors and by the loss or 
inactivation of other factors (antivirulence genes), which presumably 
occurred during these organisms’ transition from an extracellular to 
an intracellular lifestyle.
Colonization and invasion of the colonic mucosa, followed by replica­
tion therein and cell-to-cell spread (in part via a type III secretion sys­
tem), result in the development of inflammatory colitis. However, unlike 
Shigella, EIEC produces disease only with a large inoculum (108–1010 
CFU) and is less virulent, typically causing only mild, self-limited (7–10 
days), watery diarrhea. Onset generally follows an incubation period 
of 1–3 days. Occasionally, EIEC can cause a shigellosis-like (dysentery) 
syndrome characterized by fever, abdominal pain, tenesmus, and scant 
stool containing mucus, blood, and inflammatory cells.
ENTEROAGGREGATIVE AND DIFFUSELY ADHERENT E. COLI  EAEC has 
been described primarily in low- and middle-income countries and in 
young children. However, recent studies indicate that it may also be a 
relatively common cause of diarrhea in all age groups in industrialized 
countries. EAEC has been recognized increasingly as an important 
cause of traveler’s diarrhea. It is highly adapted to humans—the prob­
able reservoir. A large inoculum is required for infection, which usually 
manifests as watery and sometimes persistent diarrhea in healthy but 
also malnourished or HIV-infected hosts.
In vitro, EAEC cells exhibit a diffuse or “stacked-brick” pattern of 
adherence to small-intestine epithelial cells. Virulence factors that 
probably are necessary for disease are regulated in large part by the 
transcriptional activator AggR. The pathogenesis of EAEC disease begins 
with intestinal adherence, which results from stimulation of epithelial 
mucus production and bacterial biofilm formation, the latter mediated by 
fimbriae and possibly the mucinase Pic and dispersin. Inflammation 
ensues, resulting in epithelial cell exfoliation and intestinal secretion, 
which is mediated by the enterotoxins Pet, EAST-1, ShET1, and HlyE.
An additional enteric pathotype, DAEC, is a heterogenous group 
associated with diarrheal disease, primarily in children 2–6 years of 
age in some LMICs, and may cause traveler’s diarrhea. DAEC can also 
cause UTI. Diffuse adherence is observed on epithelial cells. The Afa/
Dr adhesins may contribute to the pathogenesis of such infections.

Diagnosis 
Acute infectious diarrhea can be classified as nonin­
flammatory or inflammatory; the latter is suggested by grossly bloody 
or mucoid stools or a positive test for fecal leukocytes, lactoferrin, or 
calprotectin (Chap. 138). ETEC, EPEC, DAEC, and EAEC cause non­
inflammatory diarrhea. Identification of these agents can be achieved 
with commercial multiplex molecular panels (e.g., the BioFire FilmArray 
Gastrointestinal Panel can detect STEC, ETEC, EPEC, EAEC, and 
EIEC). However, organism identification is rarely needed because the 
associated diseases are self-limited. ETEC causes the majority and 
EAEC a minority of cases of noninflammatory traveler’s diarrhea; here 
again, however, definitive diagnosis generally is not necessary for man­
agement (as discussed below). If diarrhea persists for >10 days despite 
treatment, Giardia or Cryptosporidium (or, in immunocompromised 
hosts, certain opportunistic pathogens) should be sought.
Because of the considerable public-health importance of STEC/
EHEC/ST-EAEC infections, including the threat of HUS, the CDC 
now recommends that all patients with community-acquired diarrhea, 
whether inflammatory or not, be evaluated for these pathogens by 
simultaneous culture (to provide an isolate for strain typing and for 
outbreak detection and control) and detection of Shiga toxin or the 
corresponding genes. The rationale for testing all cases of communityacquired diarrhea, regardless of clinical features, is that bloody stool 
and fecal white blood cells (or lactoferrin) are not reliably present with 
STEC/EHEC/ST-EAEC infection. In addition, the use of both tests 
increases diagnostic sensitivity over that with either test alone.
O157 STEC/EHEC may be identified via culture by screening for 
E. coli strains that do not ferment sorbitol, with subsequent serotyp­
ing and testing for Shiga toxin. Selective or screening media are not 
available for culture-based detection of non-O157 STEC/EHEC/
ST-EAEC strains. Detection of Shiga toxins or toxin genes via DNAbased, enzyme-linked immunosorbent, and cytotoxicity assays offers 
the advantages of rapidity and detection of non-O157 STEC/EHEC/
ST-EAEC strains. Specimens positive for toxin but culture-negative for 
O157 should be forwarded to the local or state public-health laboratory 
for specialized testing.
TREATMENT
Intestinal E. coli Infections
The mainstay of treatment for all diarrheal syndromes is replace­
ment of water and electrolytes. This measure is especially important 
for STEC/EHEC/ST-EAEC infection because appropriate volume 
expansion may protect against renal injury and improve outcome.
The use of prophylactic antibiotics to prevent traveler’s diarrhea 
generally should be discouraged, especially in light of high rates of 
antimicrobial resistance. However, in selected patients (e.g., those 
who cannot afford a brief illness or are predisposed to infection), 
the use of rifaximin, which is nonabsorbable and is well tolerated, 
is reasonable.
When stools are free of mucus and blood, early patient-initiated 
treatment of traveler’s diarrhea with a fluoroquinolone or azithro­
mycin decreases the duration of illness, and the use of loperamide 
may halt symptoms within a few hours. Although dysentery caused 
by EIEC is self-limited, antimicrobial therapy hastens the resolution 
of symptoms, particularly in severe cases. By contrast, antimicro­
bial therapy for STEC/EHEC/ST-EAEC infection (the presence of 
which is suggested by grossly bloody diarrhea without fever) should 
be avoided because antibiotics may increase the incidence of HUS 
(possibly via increased production/release of Stx). In the treatment 
of HUS, plasmapheresis is not recommended and the use of eculi­
zumab (inhibition of C5) should be limited to clinical trials.
KLEBSIELLA INFECTIONS
K. pneumoniae is the most important Klebsiella species from a medical 
standpoint, causing community-acquired, LTCF-acquired, and noso­
comial infections. K. oxytoca complex and K. (formerly Enterobacter) 
aerogenes are primarily pathogens in LTCFs and hospitals. Klebsiella 

species are broadly prevalent in the environment and colonize the 
mucosal surfaces of mammals. In healthy humans, the prevalence of 
K. pneumoniae colonization is 5–35% in the colon and 1–5% in the 
oropharynx; skin is usually colonized only transiently.

Most Klebsiella infections in Western countries are caused by “classic” 

K. pneumoniae (cKp) and occur in hospitals and LTCFs. The most 
common clinical syndromes due to cKp are pneumonia, UTI, abdomi­
nal infection, intravascular device infection, surgical site infection, 
soft tissue infection, and secondary bacteremia. cKp strains have 
gained notoriety because of their propensity for acquiring treatmentconfounding antimicrobial resistance determinants and causing both 
localized and widespread outbreaks, such as with the global spread 
of cKp strains producing NDM-group MBLs. Clonal groups 11, 15, 
101, 307, and 258, many members of which produce carbapenemases, 
are undergoing international dissemination. Transmission within or 
between institutions is common. K. pneumoniae is nearly fourfold 
more transmissible than E. coli, and, disconcertingly, carbapenemaseproducing strains are associated with increased spread compared with 
carbapenem-susceptible strains.
In addition, hypervirulent K. pneumoniae (hvKp) strains that 
are phenotypically and clinically distinct from cKp have emerged 
recently, after their initial recognition in Taiwan in 1986. Although 
hvKp infections have occurred globally in all ethnic groups, most 
cases have been reported in individuals of Asian ethnicity residing 
in countries from the Asian Pacific Rim, but also in Asians living 
in other countries. Affected individuals often have diabetes mel­
litus. These demographics raise the possibility of a locale-specific 
distribution of the organism or an increased susceptibility of Asian 
hosts, especially those who are diabetic. In contrast to the usual 
health care–associated context for cKp infections in the West, hvKp 
can cause serious life- and organ-threatening infections in younger, 
healthy individuals from the community and can spread metastati­
cally from the primary site of infection or present with multiple sites 
of infection. Of concern, recent reports from Asian countries have 
demonstrated that hvKp is responsible for an increasing number of 
health care–associated or hospital-acquired infections.
CHAPTER 166
Diseases Caused by Gram-Negative Enteric Bacilli  
hvKp infection initially was characterized and distinguished 
from traditional infections caused by cKp strains by its (1) presenta­
tion as community-acquired monomicrobial pyogenic liver abscess 

(Fig. 166-1, top), (2) occurrence in patients lacking a history of 
hepatobiliary disease, and (3) propensity for metastatic spread to 
distant sites. Subsequently, the hvKp pathotype has been recognized 
as the cause of extrahepatic abscesses and infections with or without 
liver involvement, including pneumonia; meningitis (in the absence 
of trauma or neurosurgery); endophthalmitis (Fig. 166-1, middle); 
splenic, psoas, prostatic, epidural, and brain abscesses; and necrotiz­
ing fasciitis. Survivors often suffer catastrophic morbidity, such as 
vision loss and major neurologic sequelae. Most recently, clinicians 
are faced with an even greater challenge—the confluence of antimi­
crobial resistance determinants such as carbapenemase and ESBL 
genes possessed by cKp and the virulence factors possessed by hvKp 
on the same or coexisting plasmids. The result is the evolution of 
MDR and XDR hvKp.
K. pneumoniae subspecies rhinoscleromatis is the causative agent of 
rhinoscleroma, a granulomatous mucosal upper-respiratory infection 
that progresses slowly (over months or years) and causes necrosis and 
occasionally obstruction of the nasal passages. K. pneumoniae subspe­
cies ozaenae has been implicated as a cause of chronic atrophic rhinitis 
and rarely of invasive disease in compromised hosts. K. (Calymma­
tobacterium) granulomatis, a sexually transmitted pathogen, is the 
causative agent of granuloma inguinale (donovanosis) that results in 
chronic genital ulcers (Chap. 178). These Klebsiella pathotypes are 
usually isolated from patients in tropical climates and are genomically 
distinct from both cKp and hvKp.
■
■INFECTIOUS SYNDROMES
Pneumonia 
Although cKp accounts for only a small proportion 
of cases of community-acquired pneumonia in Western countries

PART 5
Infectious Diseases
FIGURE 166-1  Hypervirulent pathotype of K. pneumoniae (hvKp). Top: Abdominal 
CT scan of a previously healthy 24-year-old Vietnamese man shows a primary liver 
abscess (red arrow) with metastatic spread to the spleen (black arrow). (Courtesy 
of Drs. Chiu-Bin Hsaio and Diana Pomakova.) Middle: A previously healthy 33-yearold Chinese man presented with endophthalmitis. (AS Shon, RP Bajwa, TA Russo: 
Hypervirulent (hypermucoviscous) Klebsiella pneumoniae: A new and dangerous 
breed. Virulence 4:107, 2013.) Bottom: A hypermucoviscous phenotype (which does 
not necessarily equate with a mucoid phenotype) has been associated with hvKp 
strains. A positive string test is shown. However, this test is not optimally sensitive 
or specific. Identification of all 5 of the biomarkers iucA, iroB, peg-344, rmpA, and 
rmpA2 is presently the most accurate means to identify hvKp.

(Chap. 131), cKp and K. oxytoca are common causes of pneumonia 
among LTCF residents and hospitalized patients because of increased 
rates of oropharyngeal colonization with these organisms in such indi­
viduals. Mechanical ventilation is an important risk factor. In Asia and 
South Africa, community-acquired pneumonia due to hvKp is becom­
ing increasingly common, rivaling Streptococcus pneumoniae, and may 
occur in younger patients with no underlying disease. Klebsiella is also 
a common cause of pneumonia in severely malnourished children in 
LMICs.
As in all pneumonias due to enteric GNB, typical manifestations 
include production of purulent sputum and evidence of airspace dis­
ease. Presentation with earlier, less extensive infection is now more 
common than is the classically described lobar infiltrate, bulging fis­
sure, and currant-jelly sputum. Pulmonary infection due to hvKp that 
has spread metastatically (e.g., from a hepatic abscess) usually includes 
nodular bilateral densities, more commonly in the lower lobes. Pulmo­
nary necrosis, pleural effusion, and empyema can occur with disease 
progression.
UTI 
cKp accounts for only 1–2% of UTI episodes among other­
wise healthy adults but for 5–17% of episodes of UTI in patients with 
anatomic and functional abnormalities of the urinary tract, including 
indwelling urinary catheter use (complicated UTI). UTI due to hvKp 
presents more commonly as renal or prostatic abscess due to bac­
teremic spread than as ascending infection from the urethra and 
bladder.
Abdominal Infection 
cKp causes a spectrum of abdominal infec­
tions similar to that caused by E. coli but is less frequently isolated 
than E. coli. hvKp is a common cause of monomicrobial communityacquired pyogenic liver abscess; in the Asian Pacific Rim, it has been 
recovered with steadily increasing frequency over the past two decades, 
replacing E. coli as the most common pathogen causing this syndrome. 
hvKp also is increasingly described as a cause of spontaneous bacterial 
peritonitis and splenic abscess.
Other Infections 
When cKp and K. oxytoca cause cellulitis or soft 
tissue infection, the process most frequently involves devitalized tissue 
(e.g., decubitus and diabetic ulcers, burn wounds) and immunocom­
promised hosts. cKp and K. oxytoca cause some cases of surgical site 
infection and nosocomial sinusitis as well as occasional cases of osteo­
myelitis contiguous to soft tissue infection, nontropical myositis, and 
meningitis (during the neonatal period and after neurosurgery). By 
contrast, hvKp has become an important cause of community-acquired 
monomicrobial necrotizing fasciitis, meningitis, endophthalmitis 
(Fig. 166-1, middle), and abscesses within the brain, subdural space, 
and epidural space, particularly in the Asian Pacific Rim but also glob­
ally. Cytotoxin-producing strains of K. oxytoca have been implicated 
as a cause of non–C. difficile antibiotic-associated hemorrhagic colitis.
Bacteremia 
Klebsiella infection at any site can produce bactere­
mia. Infections of the urinary tract, respiratory tract, and abdomen 
(especially hepatic abscess) each account for 15–30% as the source of 
Klebsiella bacteremia. Intravascular device–related infections account 
for another 5–15% of episodes, and surgical site and miscellaneous 
infections account for the rest. Klebsiella is an occasional cause of 
sepsis in neonates and of bacteremia in neutropenic patients. However, 
like other enteric GNB, Klebsiella rarely causes endocarditis or other 
endovascular infections, although endocarditis can involve extensive 
valvular destruction when it occurs.
■
■DIAGNOSIS
Klebsiellae are readily isolated and identified in the laboratory. These 
organisms usually ferment lactose, although the subspecies rhinoscle­
romatis and ozaenae are nonfermenters and are indole-negative. hvKp 
frequently possesses a hypermucoviscous phenotype (Fig. 166-1, bottom), 
although the sensitivity and specificity of the string test are less than 
optimal. Identification of all 5 of the biomarkers iucA, iroB, peg-344, 
rmpA, and rmpA2 is presently the most accurate means to identify 
hvKp in both antimicrobial sensitive and MDR isolates, although cur­
rently, this test is not routinely available.

TREATMENT
Klebsiella Infections
K. (formerly Enterobacter) aerogenes has a similar resistance profile 
to E. cloacae, the treatment of which is discussed below. K. pneu­
moniae and K. oxytoca have similar antibiotic resistance profiles; 
both are intrinsically resistant to ampicillin. The prevalence of 
acquired resistance in K. pneumoniae and K. oxytoca is generally 
>30% for amoxicillin-clavulanate, ampicillin-sulbactam, nitrofu­
rantoin, and TMP-SMX and ~10−20% for fluoroquinolones, piper­
acillin-tazobactam, fosfomycin, and omadacycline.
USNHSN data from 2015−2017 identified 25% of K. pneumoniae 
as ESBL-producing strains; higher rates are reported from Asia, 
South America, and Africa. Although prevalence of ESBL-producing 
strains is greatest in LTCF, isolates of cKp that produce CTX-M 
ESBLs are increasingly described from the community. Oral treat­
ment for infection due to ESBL-producing strains is more challeng­
ing with Klebsiella than with E. coli because of the comparatively 
poor activity of nitrofurantoin, the lesser activity of fosfomycin 
(~80%), and limited available data regarding pivmecillinam (>80%) 
and omadacycline (75–100% susceptible for ESBL-producing iso­
lates, but 60% if resistant to tetracycline).
Predictably, the ESBL-driven use of carbapenems has selected for 
strains of cKp and K. oxytoca that produce carbapenemases (8–18% 
based on the study and locale, 8.6% prevalence from 2015−2017 
USNHSN data). Treatment can be problematic for such organisms, 
especially those producing MBLs (e.g., NDM), for which the high­
est prevalences are in cKp and K. oxytoca isolates from Eastern Europe 
and Asia and among health care–associated isolates. Likewise, hvKp 
strains from Asia are also increasingly reported to produce ESBLs 
and carbapenemases.
Treatment options for carbapenem-resistant Klebsiella are similar 
to those described for E. coli and depend on the class of carbapen­
emase produced (see “Carbapenemase,” above); consultation with 
infectious disease experts is advised. For carbapenem-susceptible 
strains, the most predictably active agents include carbapenems, 
amikacin, ceftazidime-avibactam, ceftolozane-tazobactam, poly­
myxins, cefiderocol, tigecycline, eravacycline, and omadacycline. 
Empirical treatment decisions for the critically ill patient should be 
dictated by local susceptibility patterns, patient-specific risk factors, 
and the site of infection.
PROTEUS INFECTIONS
Proteus species are part of the colonic flora of a wide variety of mam­
mals, birds, fish, and reptiles. The ability of these GNB to generate 
histamine from contaminated fish has implicated them in the patho­
genesis of scombroid (fish) poisoning (Chap. 471).
P. mirabilis causes 90% of Proteus infections, which occur in the 
community, LTCFs, and hospitals. By contrast, Proteus vulgaris and 
Proteus penneri are associated primarily with infections acquired in 
LTCFs or hospitals. Correspondingly, P. mirabilis colonizes healthy 
humans (up to 50%), whereas P. vulgaris and P. penneri are isolated 
primarily from individuals with underlying disease. By far the most 
common site of Proteus infection is the urinary tract, where the prin­
cipal known urovirulence factors of Proteus include adhesins, flagella, 
IgA-IgG protease, iron acquisition systems, and urease. Proteus less 
commonly causes infection at a variety of other extraintestinal sites.
■
■INFECTIOUS SYNDROMES
UTI 
P. mirabilis causes only 1–2% of UTIs in healthy women, and 
Proteus species collectively cause only 5% of hospital-acquired UTIs. 
However, Proteus is responsible for 10–15% of cases of complicated 
UTI, primarily those associated with catheterization; indeed, Proteus 
accounts for 20–45% of urine isolates from chronically catheterized 
patients. This high prevalence is due in part to bacterial production 
of urease, which hydrolyzes urea to ammonia and results in alkaliza­
tion of the urine. In alkaline urine, organic and inorganic compounds 

precipitate, contributing to the formation of struvite and carbonate–
apatite crystals, biofilms on catheters, and/or frank calculi. Proteus 
becomes associated with the stones and biofilms; thereafter, it usually 
cannot be eradicated without removal of the stones or catheter. Over 
time, staghorn calculi may form within the renal pelvis and lead to 
obstruction and renal failure. Although biologically plausible, clinical 
support is lacking for the concept that urine samples exhibiting unex­
plained alkalinity should be cultured, and that isolation of a Proteus 
species (or other urea-splitting organism) should prompt consideration 
of an evaluation for urolithiasis.

Other Infections 
Proteus occasionally causes pneumonia (primar­
ily in LTCF residents or hospitalized patients), nosocomial sinusitis, 
intraabdominal abscesses, biliary tract infection, surgical site infec­
tion, soft tissue infection (especially decubitus and diabetic ulcers), 
and osteomyelitis (primarily contiguous); in rare cases, it causes non­
tropical myositis. In addition, Proteus uncommonly causes neonatal 
meningitis, with the umbilicus frequently implicated as the source; 
this disease is often complicated by development of a cerebral abscess. 
Otogenic brain abscess also occurs.
Bacteremia 
Most episodes of Proteus bacteremia originate from the 
urinary tract, although intravascular devices and any of the less com­
mon sites of Proteus infection also are potential sources. Endovascular 
infection is rare. Proteus species are occasional agents of sepsis in neo­
nates and of bacteremia in neutropenic patients.
■
■DIAGNOSIS
Proteus is readily isolated and identified in the laboratory. Most strains 
are lactose-negative, produce H2S, and demonstrate characteristic 
swarming motility and distinct odor on agar plates. P. mirabilis and 

P. penneri are indole-negative, whereas P. vulgaris is indole-positive. 
The inability to produce ornithine decarboxylase differentiates P. penneri 
from P. mirabilis.
CHAPTER 166
Diseases Caused by Gram-Negative Enteric Bacilli  
TREATMENT
Proteus Infections
Intrinsic resistance occurs in all Proteus spp. to nitrofurantoin, 
polymyxins, imipenem, and the tetracycline derivatives (e.g., tige­
cycline, eravacycline, omadacycline) and, in P. vulgaris and P. 
penneri, also to ampicillin and the first- and second-generation 
cephalosporins. Acquired resistance (% of isolates) occurs in P. 
mirabilis to ampicillin (15–65%), and in Proteus spp. to fluoroqui­
nolones (10–55%), fosfomycin (7–22%), and TMP-SMX (20–50%). 
In P. mirabilis, ampicillin-sulbactam is more active than ampicillin, 
with resistance rates of 6–18%, but the prevalence of ESBL produc­
tion (which confers ampicillin-sulbactam resistance) is increasing 
in the United States (5–10%) and Asia (up to 60%). Isolates of P. 
mirabilis that produce CTX-M ESBLs have been recovered from 
ambulatory patients with no recent health care contact (see the sec­
tion on the treatment of extraintestinal E. coli infections for treat­
ment considerations). Acquired carbapenem resistance remains 
relatively infrequent (<10%). However, production of MBLs (e.g., 
NDM) limits treatment options due to the inherent resistance 
of Proteus spp. to polymyxins and tetracycline derivatives (see 
“Carbapenemase,” above). For critically ill patients, agents with 
excellent activity overall against Proteus spp. (90–100% of isolates 
susceptible) include carbapenems (excepting imipenem), amikacin, 
piperacillin-tazobactam, aztreonam, cefepime, ceftazidime-avibactam, 
ceftolozane-tazobactam.
ENTEROBACTER AND CRONOBACTER 
INFECTIONS
The E. cloacae complex is responsible for most Enterobacter infections, 
whereas Cronobacter sakazakii (formerly Enterobacter sakazakii), Crono­
bacter malonaticus, E. cancerogenus, E. asburiae, E. hormaechei, E. kobei, 
E. ludwigii, and E. gergoviae are less commonly isolated (<1% for each). 
Enterobacter bugandensis has been recently described as an agent of

sepsis in neonates and was isolated from the International Space Station. 
Enterobacter spp. cause primarily health care–related infections. The 
organisms are widely prevalent in foods, environmental sources (includ­
ing equipment at health care facilities), and a variety of animals.

Colonization with these organisms is uncommon among healthy 
humans but increases significantly with LTCF residence or hospitaliza­
tion. Although colonization is an important prelude to infection, direct 
introduction via IV lines (e.g., contaminated IV fluids or pressure 
monitors) or contaminated non-FDA-approved stem cell products also 
occurs. Extensive antibiotic resistance has developed in Enterobacter 
spp. and probably has contributed to these organisms’ emergence as 
prominent nosocomial pathogens. Risk factors for Enterobacter infec­
tion include prior antibiotic treatment, comorbid disease, and ICU 
residency. Enterobacter spp. causes a spectrum of extraintestinal infec­
tions similar to those described for other GNB.
■
■INFECTIOUS SYNDROMES
The most commonly encountered syndromes include pneumonia, UTI 
(particularly catheter-associated), intravascular device–related infection, 
surgical site infection, and abdominal infection (primarily postoperative 
or related to devices such as biliary stents). Nosocomial sinusitis, men­
ingitis related to neurosurgical procedures (including use of intracranial 
pressure monitors), osteomyelitis, and endophthalmitis after eye surgery 
are less frequent. Neonates (particularly if low-birth-weight) are at risk 
for C. sakazakii infection, including neonatal bacteremia, necrotiz­
ing enterocolitis, and meningitis (which is often complicated by brain 
abscess or ventriculitis). Contaminated powdered infant formula has 
been implicated as a source for such neonatal infections. The WHO 
recommends that, to reduce the initial number of bacteria, powdered 
infant formula should be reconstituted with hot water (>70°C) and, to 
limit replication of residual bacteria, the reconstituted formula should be 
stored at <5°C or its storage time minimized.
PART 5
Infectious Diseases
Enterobacter bacteremia can result from primary infection at any 
anatomic site. In bacteremia of unclear origin, particularly in an out­
break setting, sources for consideration should include contaminated 
IV fluids or medications, blood components or plasma derivatives, 
catheter-flushing fluids, pressure monitors, and dialysis equipment. 
Enterobacter can also cause bacteremia in neutropenic patients. Entero­
bacter endocarditis is rare, occurring primarily in association with IV 
drug use or prosthetic valves.
■
■DIAGNOSIS
Enterobacter is readily isolated and identified in the laboratory. Most 
strains are lactose-positive and indole-negative.
TREATMENT
Enterobacter Infections
E. cloacae is intrinsically resistant to ampicillin, ampicillin-sulbac­
tam, ampicillin-clavulanate, the first-generation cephalosporins, 
and the cephamycins. The prevalence of acquired resistance has 
ranged from 15 to 40% for piperacillin-tazobactam, 5 to 23% for 
polymyxins, 15 to 17% for fosfomycin, 15 to 30% for TMP-SMX, 
and 5 to 20% for fluoroquinolones and is ~10% for omadacycline 
(53% if tetracycline resistant). USNHSN data from 2015−2017 
identified at least 9% of E. cloacae isolates as presumptively ESBLproducing, based on cefepime resistance. The prevalence of ESBLs 
in E. cloacae outside of the United States is 20−50%. The use of 
third-generation cephalosporins can induce or select for stable derepression of AmpC β-lactamase. Because resistance may emerge 
during therapy (in one study, this phenomenon was documented 
in 20% of clinical isolates), these agents should be avoided in the 
treatment of severe Enterobacter infection.
Cefepime is stable to hydrolysis by AmpC β-lactamases; thus, it 
is a suitable option for treatment of Enterobacter infections so long 
as ESBL is not co-produced. Overall, resistance prevalence generally 
ranges from 10 to 25% for cefepime and 25 to 50% for aztreonam and 
the third-generation cephalosporins. Carbapenem resistance remains 
relatively uncommon (USNHSN data from 2015−2017 identified a 

5% prevalence) and is more commonly associated with a combina­
tion of increased AmpC expression and decreased permeability due 
to porin mutations rather than carbapenemase production, although 
acquisition of carbapenemase genes is increasing (see “Carbapen­
emase,” above). Uncertainty exists on the optimal treatment for 
non-CP-CR-Enterobacter spp. Fortunately, overall, the percentage of 
susceptibility is high (90–99%) for carbapenems, amikacin, ceftazi­
dime-avibactam, cefiderocol, tigecycline, eravacycline, and omada­
cycline (the latter three for tetracycline-susceptible isolates). Once 
susceptibility data for a patient’s isolate become available, de-escalation 
of the antimicrobial regimen is advisable whenever possible.
SERRATIA INFECTIONS
S. marcescens causes >90%, and Serratia liquefaciens complex <10%, of 
Serratia infections. Serratiae are found primarily in the environment 
(including in health care institutions), particularly in moist settings. 
Serratiae have been isolated from a variety of animals, insects, and 
plants, but only infrequently from healthy humans. In LTCFs and 
hospitals, reservoirs for the organisms include the hands and finger­
nails of health care personnel, food, milk (on neonatal units), sinks, 
medical equipment or devices, IV solutions or parenteral medications 
(particularly those generated by compounding pharmacies), prefilled 
syringes and multiple-access medication vials (e.g., for heparin, pro­
pofol, saline), blood products (e.g., platelets), hand soaps and lotions, 
irrigation solutions, and even disinfectants such as chlorhexidine.
Infection results from either direct inoculation (e.g., via con­
taminated injected substances [IV fluids, medications, or recreational 
drugs] or snake bite) or colonization (primarily of the respiratory 
tract). Sporadic infection is most common, but outbreaks (often 
involving MDR strains in adult and neonatal ICUs) also occur. 
Hygiene, medication-compounding standards, sterile technique, and 
infection control programs are critical measures to prevent infection.
The spectrum of extraintestinal infections caused by Serratia is 
similar to that for other GNB. Serratia species are usually considered to 
cause mainly health care–associated infections; they account for 1–3% 
of hospital-acquired infections. However, population-based laboratory 
surveillance studies in Canada and Australia have demonstrated that 
community-acquired Serratia infections occur more commonly than 
was previously appreciated, and case reports have documented serious 
infection in otherwise healthy hosts. Serratia also is one of the patho­
gens associated with chronic granulomatous disease.
■
■INFECTIOUS SYNDROMES
The most common primary sites of Serratia infection are the respira­
tory and genitourinary tracts, intravascular devices, the eye (contact 
lens–associated keratitis and other ocular infections), surgical wounds, 
and the bloodstream (from contaminated infusions), although most 
episodes of Serratia bacteremia arise from one of the listed focal infec­
tions rather than contaminated infusate. Less common syndromes are 
soft tissue infections (including myositis, fasciitis, mastitis), osteomy­
elitis, abdominal and biliary tract infections (usually postprocedural), 
and septic arthritis (primarily from intraarticular injections). Serratiae 
are uncommon causes of neonatal meningitis; postsurgical meningitis, 
endophthalmitis, or breast implant infection; and bacteremia in neu­
tropenic patients. Endocarditis is rare, occurring most commonly in 
IV drug users.
■
■DIAGNOSIS
Serratiae are readily cultured and identified by the laboratory and are 
usually lactose- and indole-negative. The red pigmentation of some 

S. marcescens strains and Serratia rubidaea can produce distinctive clin­
ical findings (e.g., pink breast milk or hypopyon; pseudohemoptysis).
TREATMENT
Serratia Infections
Most Serratia strains (>80%) are intrinsically resistant to ampi­
cillin, amoxicillin-clavulanate, ampicillin-sulbactam, first- and

second-generation cephalosporins, cephamycins, nitrofurantoin, 
and polymyxins; likewise, tetracycline derivatives are poorly active. 
By contrast, fluoroquinolones, TMP-SMX, piperacillin-tazobactam, 
fosfomycin, and omadacycline are active against 85−95% of U.S. 
and European isolates, including those resistant to tetracycline. 
Both in the United States and globally, the prevalence of ESBLproducing isolates is generally low (<10%), but rates of 20–30% 
have been reported in Asia and Latin America. Induction or selec­
tion of variants with stable de-repression of chromosomal AmpC 
β-lactamases during therapy with third-generation cephalosporins 
is considered to be uncommon. Resistance prevalence generally 
ranges from 10 to 20% for aztreonam and the third-generation 
cephalosporins. Acquisition of carbapenemase-encoding genes is 
uncommon but increasing. Production of MBL (e.g., NDM) limits 
treatment options due to Serratia’s predictable resistance to poly­
myxins and tetracycline derivatives (see “Carbapenemase,” above). 
For critically ill patients, the most active agents overall (>90% 
susceptible) are carbapenems, piperacillin-tazobactam, cefepime, 
amikacin, ceftazidime-avibactam, and ceftolozane-tazobactam.
CITROBACTER INFECTIONS
C. freundii and Citrobacter koseri cause most human Citrobacter infec­
tions, which are epidemiologically and clinically similar to Entero­
bacter infections. Citrobacter species are commonly present in water, 
food, soil, and certain animals. Colonization with these organisms is 
uncommon among healthy humans but increases significantly with 
LTCF residence or hospitalization. Citrobacter species account for 
1–2% of nosocomial infections. The affected hosts are usually immu­
nocompromised and/or have comorbid disease or disruption of skin 
or mucosal barriers. Infection from treatment with contaminated, 
non-FDA-approved stem cell products has been described. Citrobacter 
causes extraintestinal infections like those described for other GNB.
■
■INFECTIOUS SYNDROMES
The urinary tract accounts for 40–50% of Citrobacter infections. Less 
commonly involved sites include the biliary tree (particularly with 
stones or obstruction), the respiratory tract, surgical sites, soft tissue 
(e.g., decubitus ulcers), the peritoneum, and intravascular devices. 
Osteomyelitis (usually from a contiguous focus), central nervous sys­
tem infection in adults (from neurosurgical or other types of meningeal 
disruption), and myositis occur rarely. Citrobacter (primarily C. koseri) 
also causes 1–2% of neonatal meningitis cases, of which 50–80% are 
complicated by brain abscess. Further, case reports in adults suggest 
that C. koseri infection has a predilection for abscess formation. Citro­
bacter bacteremia is most often due to UTI, biliary/abdominal infec­
tion, or intravascular device infection, and occurs in some neutropenic 
patients. Endocarditis and other endovascular infections are rare.
■
■DIAGNOSIS
Citrobacter species are readily isolated and identified; 35–50% of iso­
lates are lactose-positive, and 100% are oxidase-negative. C. freundii is 
indole-negative, whereas C. koseri is indole-positive.
TREATMENT
Citrobacter Infections
C. freundii is more antibiotic-resistant than is C. koseri. Most C. 
freundii isolates are intrinsically resistant to ampicillin, ampicillinsulbactam, amoxicillin-clavulanate, first-generation cephalospo­
rins, and cephamycins. C. koseri exhibits intrinsic resistance to 
ampicillin and ampicillin-sulbactam. Overall, the prevalence of 
acquired resistance generally ranges from 15 to 35% for third-gen­
eration cephalosporins, piperacillin-tazobactam, fluoroquinolones, 
and TMP-SMX and is ~10% for nitrofurantoin and omadacycline 
(but 39% for omadacycline if tetracycline-resistant). The prevalence 
of ESBL production ranges from 5 to 30%. The use of third-generation 
cephalosporins may result in the induction or selection of variants 
with stable de-repression of chromosomal AmpC β-lactamases 

during therapy. Presently, <10% of isolates have acquired car­
bapenemases (see “Carbapenemase,” above). Carbapenems, ami­
kacin, fosfomycin, polymyxins, cefepime, ceftolozane-tazobactam, 
ceftazidime-avibactam, cefiderocol, tigecycline, eravacycline, and 
omadacycline (the latter three if tetracycline-susceptible) are the 
most active agents against Citrobacter isolates (>90% susceptible).

MORGANELLA AND PROVIDENCIA 
INFECTIONS
M. morganii, Providencia stuartii, and (less frequently) Providencia 
rettgeri are the members of their respective genera that cause systemic 
human infections. P. alcalifaciens has been implicated as a cause of 
food-borne gastroenteritis. These organisms’ epidemiologic asso­
ciations, pathogenic properties, and clinical manifestations resemble 
those of Proteus species. Morganella and Providencia occur more 
commonly among LTCF residents than among hospitalized patients, 
largely resulting from chronic urinary catheter use. Because of these 
organisms’ intrinsic resistance to polymyxins and tigecycline, they may 
become more common in settings with extensive use of these agents.
■
■INFECTIOUS SYNDROMES
These species are primarily urinary tract pathogens, causing UTIs that 
are most often associated with long-term (>30-day) catheterization. 
Such infections commonly lead to biofilm formation and catheter 
encrustation (sometimes causing catheter obstruction) or the devel­
opment of struvite bladder or renal stones (sometimes causing renal 
obstruction, abscess, and extrarenal extension, and serving as foci for 
relapse). They can cause purple urine (“purple bag syndrome”), as can 
P. mirabilis, K. pneumoniae, E. coli, and P. aeruginosa. Morganella is also 
commonly isolated from snakebite infection.
CHAPTER 166
Other, less common infectious syndromes due to Morganella and 
Providencia include surgical site infection, soft tissue infection (pri­
marily involving decubitus and diabetic ulcers), burn site infection, 
pneumonia (particularly ventilator-associated), intravascular device 
infection, and intraabdominal infection. Rarely, the other extraintesti­
nal infections described for GNB also occur. Bacteremia is uncommon; 
when it does occur, any infected site can serve as the source, but the 
urinary tract accounts for most cases, followed by surgical site, soft tis­
sue, and hepatobiliary infections.
Diseases Caused by Gram-Negative Enteric Bacilli  
■
■DIAGNOSIS
M. morganii and Providencia are readily isolated and identified. Nearly 
all isolates are lactose-negative and indole-positive.
TREATMENT
Morganella and Providencia Infections
Morganella and Providencia are intrinsically resistant to ampicil­
lin, ampicillin-clavulanate, ampicillin-sulbactam, first-generation 
cephalosporins, nitrofurantoin, tetracyclines and derivatives (e.g., 
tigecycline), imipenem (but not the other carbapenems), and the 
polymyxins. P. stuartii additionally exhibits intrinsic resistance to 
gentamicin and tobramycin, as does M. morganii to second-generation 
cephalosporins. Fosfomycin is poorly active (>50% resistance). The 
prevalence of resistance generally ranges from 10 to 30% for the 
third-generation cephalosporins, from 10 to 40% for fluoroquino­
lones, and from 20 to 40% for TMP-SMX; the prevalence is more 
widely variable for piperacillin-tazobactam. The prevalence of ESBL 
production is generally <10%. The prevalence of acquired car­
bapenemase production is <10%. Production of MBL (e.g., NDM) 
limits treatment options due to the inherent resistance of Proteeae 
to polymyxins and tetracycline derivatives (see “Carbapenemase,” 
above). Overall, the most active agents (>90% of isolates suscep­
tible) are carbapenems (excepting imipenem), amikacin, cefepime, 
ceftazidime-avibactam, ceftolozane-tazobactam, and cefiderocol. 
Removal of a colonized urinary catheter or stone is critical for 
eradication of UTI.