1258 PART 5 Infectious Diseases

cyclase-hemolysin toxin, which impairs host phagocytic cell function;

dermonecrotic toxin, which may contribute to respiratory mucosal

damage; and lipooligosaccharide, which has properties similar to those

of other gram-negative bacterial endotoxins. Since 2010, the emergence of pertactin-negative strains has been observed worldwide, and

these strains now predominate in some regions, perhaps from immune

pressure resulting from the use of pertactin-containing acellular pertussis vaccines.

■ EPIDEMIOLOGY

Pertussis is a highly communicable disease, with attack rates of

80–100% among unimmunized household contacts and 20% within

households in well-immunized populations. The infection has a worldwide distribution, with cyclical outbreaks every 3–5 years (a pattern

that has persisted despite widespread immunization). Pertussis occurs

in all months; however, in North America, its activity peaks in autumn

and winter.

In developing countries, pertussis remains an important cause of

infant morbidity and death. The reported incidence of pertussis worldwide has decreased as a result of improved vaccine coverage (Fig. 160-1).

However, coverage rates are still <60% in many developing nations; the

World Health Organization (WHO) estimates that 90% of the burden

of pertussis is in developing regions. In addition, over-reporting of

immunization coverage and under-reporting of disease result in substantial underestimation of the global burden of pertussis. The WHO

estimates that there were 161,000 deaths from pertussis among children <5 years of age in 2014.

Before the institution of widespread immunization programs in the

developed world, pertussis was one of the most common infectious

causes of morbidity and death. In the United States before the 1940s,

between 115,000 and 270,000 cases of pertussis were reported annually,

with an average yearly rate of 150 cases per 100,000 population. With

universal childhood immunization, the number of reported cases fell

by >90%, and mortality rates decreased even more dramatically. Only

1010 cases of pertussis were reported in 1976 (Fig. 160-2). After that

historic low, rates of pertussis increased slowly. In recent years, pertussis epidemics have been reported with increasing frequency in highincome countries, including Australia, the United Kingdom, and the 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

0

0.5M

1M

Immunization coverage (%)

Number of cases

1.5M

2M

Pertussis global annual reported cases and DTP3 coverage 1980-2019

Number of cases Official coverage WHO/UNICEF estimates

100

90

80

70

60

50

40

30

20

10

0

FIGURE 160-1 Global annual reported cases of pertussis and rate of coverage with DTP3 (diphtheria toxoid, tetanus toxoid, and pertussis vaccine; 3 doses), 1980–2019.

(Reproduced from www.who.int/immunization/monitoring_surveillance/burden/vpd/surveillance_type/passive/pertussis_coverage_2019.jpg. World Health Organization;

2019. License: CC BY-NC-SA 3.0 IGO. Accessed June 4, 2021.)

United States. The United States experienced widespread outbreaks of

pertussis in 2005, 2010, 2012, and 2014 at levels not seen in 40–50 years

(48,000 reported cases in 2012).

Although thought of as a disease of childhood, pertussis can affect

people of all ages and is a known cause of prolonged coughing illness

in adolescents and adults. In unimmunized populations, pertussis incidence peaks during the preschool years, and well over half of children

have the disease before reaching adulthood. In highly immunized populations such as those in North America, the peak incidence is among

infants <1 year of age who have not completed the three-dose primary

immunization series. An increase in pertussis incidence among adolescents and adults began in the late 1990s and led to the introduction

of an adolescent booster dose across North America by 2006. While

the disease burden among adolescents decreased initially, children

7–10 years of age emerged as a high-risk group during a major outbreak in 2010. Most of the affected children were fully immunized.

Subsequent outbreaks in 2012 and 2014 showed a shift in epidemiology, with pertussis incidence increasing among adolescents while

still remaining elevated among 10-year-olds. The most highly affected

cohorts were those who received acellular pertussis vaccines in infancy.

Although adults contribute a smaller proportion of reported cases

of pertussis than do children and adolescents, this difference may be

related to a greater degree of under-recognition and under-reporting.

A number of studies of prolonged coughing illness suggest that B. pertussis may be the etiologic agent in 12–30% of adults with cough that

does not improve within 2 weeks. In one study of the efficacy of an

acellular pertussis vaccine in adolescents and adults, the incidence of

pertussis in the placebo group was 3.7–4.5 cases per 1000 person-years.

Although this prospective cohort study yielded a lower estimate than

the studies of cough illness, its results still translate to ~1 million cases

of pertussis annually among adults in the United States. In addition,

asymptomatic pertussis infection is common and appears to contribute

to disease transmission.

Severe morbidity and high mortality rates, however, are restricted

almost entirely to infants. In the United States between 2008 and

2011, 83% of pertussis deaths involved infants ≤3 months and >35%

of infants with pertussis required hospitalization. Although school-age

children are the source of infection for most households, adults are

1259CHAPTER 160 Pertussis and Other Bordetella Infections

0

10000

20000

30000

40000

50000

60000

1976 1981 1986 1991 1996 2001 2006 2011 2016

Number of reported cases

Year

FIGURE 160-2 Reported cases of pertussis by year—United States, 1976–2019. (From the Centers for Disease Control and Prevention, www.cdc.gov/pertussis/

surv-reporting/cases-by-year.html. Accessed June 4, 2021.)

often the source for cases in high-risk infants and may serve as the

reservoir of infection between epidemic years.

■ PATHOGENESIS

Infection with B. pertussis is initiated by attachment of the organism to

the ciliated epithelial cells of the nasopharynx. Attachment is mediated

by surface adhesins (e.g., pertactin and filamentous hemagglutinin),

which bind to the integrin family of cell-surface proteins, probably

in conjunction with pertussis toxin. The role of fimbriae in adhesion

and in maintenance of infection has not been fully delineated. Perhaps

the result of redundancy of adhesins, no differences in virulence or

clinical manifestations have been detected with the emergence of

pertactin-negative strains. At the site of attachment, the organism

multiplies, producing a variety of other toxins that cause local mucosal

damage (tracheal cytotoxin, dermonecrotic toxin). Impairment of host

defense by B. pertussis is mediated by pertussis toxin and adenylate

cyclase-hemolysin toxin. There is local cellular invasion, with intracellular bacterial persistence; however, systemic dissemination does not

occur. Systemic manifestations (lymphocytosis) result from the effects

of the toxins.

The pathogenesis of the clinical manifestations of pertussis is poorly

understood. It is not known what causes the hallmark paroxysmal

cough. A pivotal role for pertussis toxin has been proposed but has

not been confirmed. It is thought that neurologic events in pertussis,

such as seizures and encephalopathy, are due to hypoxia from coughing paroxysms or apnea rather than to the effects of specific bacterial

products. B. pertussis pneumonia, which occurs in up to 10% of infants

with pertussis, is usually a diffuse bilateral primary infection. In older

children and adults with pertussis, pneumonia is often due to secondary bacterial infection with streptococci or staphylococci. Deaths from

pertussis among young infants are frequently associated with very high

levels of leukocytosis and pulmonary hypertension.

■ IMMUNITY

Both humoral and cell-mediated immunity are thought to be important in pertussis. Although immunity after natural infection was

thought to be lifelong, seroepidemiologic evidence demonstrates that

it is not and that subsequent episodes of clinical pertussis are prevented

by intermittent subclinical infection. Pertussis agglutinins were correlated with protection in early studies of whole-cell pertussis vaccines.

Antibodies to pertussis toxin, filamentous hemagglutinin, pertactin,

and fimbriae are all protective in animal models. Serologic correlates

of protection conferred by acellular pertussis vaccines have not been

established, although antibody to pertactin, fimbriae, and (to a lesser

degree) pertussis toxin correlated best with protection in two efficacy

trials. The duration of immunity after whole-cell pertussis vaccination

is short-lived, with little protection remaining after 10–12 years. Waning of immunity is even more rapid in adolescents and children who

have received all of their immunizations with acellular vaccines—i.e.,

within 2–4 years after the fifth or sixth dose. The type of immune

response elicited may have an effect on duration of protection; natural

infection and whole-cell pertussis vaccine elicit a Th1/Th17-predominant response whereas acellular pertussis vaccines stimulate a Th2-

biased response.

■ CLINICAL MANIFESTATIONS

Pertussis is a prolonged coughing illness with clinical manifestations

that vary by age (Table 160-1). Although not uncommon among adolescents and adults, classic pertussis is most often seen in preschool and

school-age children. After an incubation period averaging 7–10 days,

an illness develops that is indistinguishable from the common cold and

is characterized by coryza, lacrimation, mild cough, low-grade fever,

and malaise. After 1–2 weeks, this catarrhal phase evolves into the

paroxysmal phase: the cough becomes more frequent and spasmodic

with repetitive bursts of 5–10 coughs, often within a single expiration.

Post-tussive vomiting is frequent, with a mucous plug occasionally

expelled at the end of an episode. The episode may be terminated by an

audible whoop, which occurs upon rapid inspiration against a closed

glottis at the end of a paroxysm. During a spasm, there may be impressive neck-vein distension, bulging eyes, tongue protrusion, and cyanosis. Paroxysms may be precipitated by noise, eating, or physical contact.

TABLE 160-1 Clinical Features of Pertussis, by Age Group and

Diagnostic Status

PERCENTAGE OF PATIENTS

FEATURE

ADOLESCENTS AND

ADULTS INFANTS AND CHILDREN

Cough

Paroxysmal 70–99 89–93

Worse at night 61–87 41

Whoop 8–82 69–92

Post-tussive vomiting 17–65 48–60

Source: Republished with permission of American Society for Microbiology from

Pertussis: Microbiology, disease, treatment, and prevention, PE Kilgore et al: 29:449,

2016; permission conveyed through Copyright Clearance Center, Inc.

1260 PART 5 Infectious Diseases

Between attacks, the patient’s appearance is normal, but increasing

fatigue is evident. The frequency of paroxysmal episodes varies widely,

from several per hour to 5–10 per day. Episodes are often worse at night

and interfere with sleep. Most complications occur during the paroxysmal stage. Fever is uncommon and suggests bacterial superinfection.

After 2–4 weeks, the coughing episodes become less frequent and

less severe—changes heralding the onset of the convalescent phase. This

phase can last 1–3 months and is characterized by gradual resolution of

coughing episodes. For 6–12 months, intercurrent viral infections may

be associated with a recrudescence of paroxysmal cough.

Not all individuals who develop pertussis have classic disease. The

clinical manifestations in adolescents and adults are more often atypical. The cough is severe, prolonged, and often paroxysmal. Though

uncommon, a whoop and vomiting with cough are more specific signs

of pertussis in adults with prolonged cough. Other suggestive features

are a cough at night, sweating episodes between paroxysms of coughing, and exposure to other individuals with a prolonged coughing

illness.

■ COMPLICATIONS

Complications are frequently associated with pertussis and are more

common among infants than among older children or adults. Subconjunctival hemorrhages, abdominal and inguinal hernias, pneumothoraces, and facial and truncal petechiae can result from increased

intrathoracic pressure generated by severe fits of coughing. Weight loss

can follow decreased caloric intake. Urinary incontinence, rib fracture,

carotid artery aneurysm, and cough syncope have also been reported

in adolescents and adults with pertussis. In a series of more than 1100

children <2 years of age who were hospitalized with pertussis, 27.1%

had apnea, 9.4% had pneumonia, 2.6% had seizures, and 0.4% had

encephalopathy; 10 children (0.9%) died. Pneumonia is reported in

<5% of adolescents and adults and increases in frequency after 50 years

of age. In contrast to the primary B. pertussis pneumonia that develops

in infants, pneumonia in adolescents and adults with pertussis is usually caused by a secondary infection with encapsulated organisms such

as Streptococcus pneumoniae or Haemophilus influenzae.

■ DIAGNOSIS

If the classic symptoms of pertussis are present, clinical diagnosis is

not difficult. However, particularly in older children and adults, it is

difficult to differentiate infections caused by B. pertussis and B. parapertussis from other respiratory tract infections on clinical grounds.

Therefore, laboratory confirmation should be attempted in all cases.

Lymphocytosis (absolute lymphocyte count >108

–109

/L) is common

among young children, in whom it is unusual with other infections,

but not among adolescents and adults. Culture of nasopharyngeal

secretions remains the gold standard of diagnosis because of its 100%

specificity, although DNA detection by PCR has replaced culture in

many laboratories because of substantially increased sensitivity and

quicker results. Appropriate PCR methodology must include primers

to differentiate among B. pertussis, B. parapertussis, and B. holmesii. The best specimen is collected by nasopharyngeal aspiration, in

which a fine flexible plastic catheter attached to a 10-mL syringe is

passed into the nasopharynx and withdrawn while gentle suction is

applied. Since B. pertussis is highly sensitive to drying, secretions for

culture should be inoculated without delay onto appropriate medium

(Bordet-Gengou or Regan-Lowe), or the catheter should be flushed

with a phosphate-buffered saline solution for culture and/or PCR. An

alternative to the aspirate is a Dacron or rayon nasopharyngeal swab;

again, inoculation of culture plates should be immediate or an appropriate transport medium (e.g., Regan-Lowe charcoal medium) should

be used. Results of PCR can be available within hours; cultures become

positive by day 5 of incubation.

Nasopharyngeal cultures in untreated pertussis remain positive

for a mean of 3 weeks after the onset of illness; these cultures become

negative within 5 days of the institution of appropriate antimicrobial

therapy. The duration of a positive PCR in untreated pertussis or after

therapy is not known but exceeds that of positive cultures. Since much

of the period during which the organism can be recovered from the

nasopharynx falls into the catarrhal phase, when the etiology of the

infection is not suspected, there is only a small window of opportunity

for culture-proven diagnosis. Cultures from infants and young children

are more frequently positive than those from older children and adults;

this difference may reflect earlier presentation of the former age group

for medical care. Direct fluorescent antibody tests of nasopharyngeal

secretions for direct diagnosis may still be available in some laboratories but should not be used because of poor sensitivity and specificity.

As a result of the difficulties with laboratory diagnosis of pertussis

in adolescents, adults, and patients who have been symptomatic for

>4 weeks, increasing attention is being given to serologic diagnosis.

Enzyme immunoassays detecting IgA and IgG antibodies to pertussis

toxin, filamentous hemagglutinin, pertactin, and fimbriae have been

developed and assessed for reproducibility. Two- or fourfold increases

in antibody titer are suggestive of pertussis, although cross-reactivity

of some antigens (such as filamentous hemagglutinin and pertactin)

among Bordetella species makes it difficult to depend diagnostically

on seroconversion involving a single type of antibody. Criteria for

serologic diagnosis based on comparison of results for a single serum

specimen with established population values are gaining acceptance,

and serologic measurement of antibody to pertussis toxin is becoming

more widely standardized and available for diagnostic purposes, particularly in outbreak settings and for surveillance.

■ DIFFERENTIAL DIAGNOSIS

A child presenting with paroxysmal cough, post-tussive vomiting, and

whoop is likely to have an infection caused by B. pertussis or B. parapertussis; lymphocytosis increases the likelihood of a B. pertussis etiology.

Viruses such as respiratory syncytial virus, rhinovirus, and adenovirus

have been isolated from patients with clinical pertussis but probably

represent co-infection, particularly in children <1 year of age.

In adolescents and adults, who often do not have paroxysmal cough

or whoop, the differential diagnosis of a prolonged coughing illness is

more extensive. Pertussis should be suspected when any patient has a

cough that does not improve within 14 days, a paroxysmal cough of

any duration, a cough followed by vomiting (adolescents and adults),

or any respiratory symptoms after contact with a laboratory-confirmed

case of pertussis. Other etiologies to consider include infections caused

by Mycoplasma pneumoniae, Chlamydia pneumoniae, adenovirus,

influenza virus, and other respiratory viruses. Use of angiotensinconverting enzyme (ACE) inhibitors, reactive airway disease, and gastroesophageal reflux disease are well-described noninfectious causes of

prolonged cough in adults.

TREATMENT

Pertussis

ANTIBIOTICS

The purpose of antibiotic therapy for pertussis is to eradicate the

infecting bacteria from the nasopharynx; therapy does not substantially alter the clinical course unless given early in the catarrhal

phase. Macrolide antibiotics are the drugs of choice for treatment of

pertussis (Table 160-2); macrolide-resistant B. pertussis strains have

been reported but are rare. Trimethoprim-sulfamethoxazole is recommended as an alternative for individuals allergic to macrolides.

SUPPORTIVE CARE

Young infants have the highest rates of complication and death

from pertussis; therefore, most infants (and older children with

severe disease) should be hospitalized. A quiet environment may

decrease the stimulation that can trigger paroxysmal episodes. Use

of β-adrenergic agonists and/or glucocorticoids has been advocated

by some authorities but has not been proven to be effective. Cough

suppressants are not effective and play no role in the management

of pertussis.

INFECTION CONTROL MEASURES

Hospitalized patients with pertussis should be placed in respiratory

isolation, with the use of precautions appropriate for pathogens

1261CHAPTER 161 Diseases Caused by Gram-Negative Enteric Bacilli

spread by large respiratory droplets. Isolation should continue for

5 days after initiation of macrolide therapy or, in untreated patients,

for 3 weeks (i.e., until nasopharyngeal cultures are consistently

negative).

■ PREVENTION

Chemoprophylaxis Because the risk of transmission of B. pertussis within households is high, chemoprophylaxis is widely recommended for household contacts of pertussis cases regardless of their

immunization status and should be initiated within 21 days of cough

onset in the index case. The effectiveness of chemoprophylaxis is

supported by several epidemiologic studies of institutional and community outbreaks. In the only randomized, placebo-controlled study,

erythromycin estolate (50 mg/kg per day; maximum dose, 1 g/d) was

effective in reducing the incidence of bacteriologically confirmed pertussis by 67%; however, there was no decrease in the incidence of clinical disease. Despite these results, authorities continue to recommend

chemoprophylaxis, particularly in households with members at high

risk of severe disease (children <1 year of age, pregnant women). Data

on the use of the newer macrolides for chemoprophylaxis are not available, but these drugs are commonly used because of their increased

tolerability and their effectiveness.

Immunization (See also Chap. 123) The mainstay of pertussis

prevention is active immunization. Pertussis vaccine became widely

used in North America after 1940; the reported number of pertussis

cases subsequently fell by >90%. Whole-cell pertussis vaccines are prepared through the heating, chemical inactivation, and purification of

whole B. pertussis organisms. Despite their efficacy (average estimate,

85%; range for different products, 30–100%), whole-cell pertussis

vaccines are associated with adverse events—both common (fever;

injection-site pain, erythema, and swelling; irritability) and uncommon (febrile seizures, hypotonic-hyporesponsive episodes). Alleged

associations of whole-cell pertussis vaccine with encephalopathy,

sudden infant death syndrome, and autism, although not substantiated, spawned an active anti-immunization lobby. The development

of acellular pertussis vaccines, which are effective and less reactogenic,

has greatly alleviated concerns about the inclusion of pertussis vaccine

in the combined infant immunization series.

Although a wide variety of acellular pertussis vaccines were developed, only a few are still marketed widely; all contain pertussis toxoid

and filamentous hemagglutinin. One acellular pertussis vaccine also

contains pertactin, and another contains pertactin and two types of

fimbriae. Adult formulations of acellular pertussis vaccines have been

shown to be safe, immunogenic, and efficacious in clinical trials in

adolescents and adults and are now recommended for routine immunization of these groups in several countries.

Although whole-cell vaccines are still used extensively in developing

regions of the world, acellular pertussis vaccines are used exclusively

for childhood immunization in much of the developed world. In light

of evidence of early waning of immunity among children who received

acellular pertussis vaccine in infancy, the WHO Strategic Advisory

Group of Experts (SAGE) recommends that countries using whole-cell

pertussis vaccine for the primary infant immunization series continue

to do so. In countries using acellular pertussis vaccines in infancy, additional booster immunizations in older children, adolescents, and adults

are recommended to prevent pertussis in high-risk infants. Pertussis

immunization is also recommended during pregnancy to increase passive transfer of maternal antibodies to the fetus. Studies in high-income

countries demonstrate that immunization of women during pregnancy

is 90–93% effective at preventing pertussis in infants <2 months of age

and is safe. In North America, acellular pertussis vaccines for children

are given as a three-dose primary series at 2, 4, and 6 months of age,

with a reinforcing dose at 15–18 months of age and a booster dose at

4–6 years of age. Adolescents (11–18 years of age) and all unvaccinated

adults should receive a dose of the adult-formulation diphtheria–

tetanus–acellular pertussis vaccine. Immunization is specifically recommended for health care providers, individuals in close contact with

infants, and women during the third trimester of every pregnancy. Pertussis vaccine coverage among U.S. adolescents was 86.4% in 2015, and

coverage among pregnant women was 48.8% in 2015–2016. However,

coverage among adults remains low (23.1% in 2015). Further improvements in adult vaccine coverage may permit better control of pertussis

across the age spectrum, with collateral protection of infants too young

to be immunized. However, more effective vaccines with longer-lasting

protection will ultimately be needed to control this disease.

■ FURTHER READING

De Serres G et al: Morbidity of pertussis in adolescents and adults.

J Infect Dis 182:174, 2000.

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 Advisory

Committee on Immunization Practices—United States, 2019. MMWR

Morb Mortal Wkly Rep 69:77, 2020.

Kilgore PE et al: Pertussis: Microbiology, disease, treatment, and prevention. Clin Microbiol Rev 29:449, 2016.

Skoff TH: Sources of infant pertussis infection in the United States.

Pediatrics 136:635, 2015.

Winter K et al: Pertussis in California: A tale of 2 epidemics. Pediatr

Infect Dis J 37:324, 2018.

TABLE 160-2 Antimicrobial Therapy for Pertussis

DRUG ADULT DAILY DOSE FREQUENCY DURATION, DAYS COMMENTS

Erythromycin estolate 500 mg 3–4 times per day 7–14 Frequent gastrointestinal side effects

Clarithromycin 500 mg Twice a day 7 —

Azithromycin 500 mg on day 1, 250 mg subsequently 1 daily dose 5 —

Trimethoprim-sulfamethoxazole 160 mg of trimethoprim, 800 mg of

sulfamethoxazole

Twice a day 14 For patients allergic to macrolides; data on

effectiveness limited

Source: T Tiwari et al: Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC guidelines. MMWR Recomm Rep

54(RR-14):1, 2005.

GENERAL FEATURES AND PRINCIPLES

The post-antibiotic era has begun. For most people, this is the first

time in their lives that an effective treatment for a bacterial infection

may not exist. The Enterobacteriaceae 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 Enterobacteriaceae (CRE) as

representing a threat level of “urgent” and “priority one, critical.”

161 Diseases Caused by

Gram-Negative Enteric

Bacilli

Thomas A. Russo, James R. Johnson

1262 PART 5 Infectious Diseases

Enterobacteriaceae are responsible for a significant proportion of

the deaths attributed to antimicrobial-resistant bacteria, of which an

estimated 23,000 and 25,000 occur annually in the United States and

the European Union, respectively, and three to five times as many (per

capita) in low- and middle-income countries (e.g., Thailand). These

pathogens cause a wide variety of infections involving diverse anatomic sites in both healthy and compromised hosts. Therefore, a thorough 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 family Enterobacteriaceae that commonly cause extraintestinal infections. Salmonella, Shigella, and Yersinia, which also are in the

family Enterobacteriaceae but more commonly cause gastrointestinal

infections, are discussed in Chaps. 165, 166, and 171, respectively.

■ EPIDEMIOLOGY

E. coli, Klebsiella, Proteus, Enterobacter, Serratia, Citrobacter, Morganella, Providencia, Cronobacter, and Edwardsiella are components of

the normal animal and human colonic microbiota and/or the microbiota 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

resistance. In healthy humans, E. coli is the predominant species of

GNB in the colonic microbiota, followed by Klebsiella and Proteus.

GNB (primarily E. coli, Klebsiella, and Proteus) 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 association 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 pneumonia, 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

infusates (e.g., medications, blood products, non–U.S. Food and Drug

Administration [FDA] approved stem cell products). Edwardsiella

infections are acquired through freshwater and marine environment

exposures and are most common in Southeast Asia.

■ STRUCTURE AND FUNCTION

Enteric GNB possess an extracytoplasmic outer membrane consisting

of a lipid bilayer with associated proteins, lipoproteins, and polysaccharides (capsule, lipopolysaccharide). The outer membrane interfaces

with the external environment, including the human host. A variety of

components of the outer membrane are critical determinants in pathogenesis (e.g., capsule) and antimicrobial resistance (e.g., permeability

barrier, efflux pumps). In addition, secreted products 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).

■ PATHOGENESIS

Multiple bacterial virulence factors are required for the pathogenesis

of infections caused by GNB. Possession of specialized virulence genes

defines pathogens and enables them to infect the host efficiently. Hosts

and their cognate pathogens have been co-adapting throughout evolutionary history. During the host–pathogen “chess match” over time,

various and redundant strategies have emerged in both the pathogens

and their hosts (Table 161-1).

TABLE 161-1 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

Intestinal pathogenic (diarrheagenic) mechanisms are discussed

below. The members of the Enterobacteriaceae family that cause

extraintestinal infections are primarily extracellular pathogens and

therefore share certain pathogenic features. The two principal components of host defense against Enterobacteriaceae, 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 susceptibility 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

differences in host environments, defense mechanisms, and physiological 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 siderophores) requires many genes that are necessary but not sufficient for

pathogenesis. The ability to resist the bactericidal activity of complement and phagocytes in the absence of antibody (e.g., as conferred by

capsule or 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.

The ability to induce septic shock is another defining feature of these

genera. GNB are the most common causes of this potentially lethal

syndrome. Pathogen-associated molecular pattern molecules (PAMPs;

e.g., the lipid A moiety of lipopolysaccharide) stimulate a proinflammatory host response via pattern recognition receptors (e.g., Toll-like

or C-type lectin receptors) that activate host defense signaling pathways;

if overly exuberant, this response results in shock (Chap. 304). Direct

bacterial damage of host tissue (e.g., by toxins) or collateral damage

from the host response can result in the release of damage-associated

molecular pattern molecules (DAMPs; e.g., HMGB1) that can propagate a detrimental proinflammatory host response.

Many antigenic variants (serotypes) exist in most genera of GNB.

For example, E. coli has >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. 123).

1263CHAPTER 161 Diseases Caused by Gram-Negative Enteric Bacilli

■ 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 extraintestinal infection, depending on the particular 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 extraintestinal 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 problematic 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

and the respiratory tract, requires clinical correlation to differentiate

colonization from infection. Clinical microbiology laboratories are

increasingly incorporating newer diagnostic methodologies (e.g.,

matrix-assisted laser desorption–ionization–time-of-flight mass spectrometry [MALDI-TOF-MS] and polymerase chain reaction [PCR])

and immunoassays to enhance the sensitivity, accuracy, and rapidity

of reporting on pathogen 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.

TREATMENT

Principles Guiding Treatment in the Era of

Increasing Antimicrobial Resistance

(See also Chap. 144) Initiation of appropriate empirical antimicrobial 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 susceptibility by species, geographic location, regional antimicrobial use,

and hospital site (e.g., intensive care units [ICUs] vs wards) necessitate 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). Resistance rates will almost certainly increase over time and will likely be higher than shown here

by the time this chapter is published. Of concern are an increasing

number of reports on resistant Enterobacteriaceae 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 foreign 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 as a way 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 susceptibility results become available. Such responsible antimicrobial

stewardship should help disrupt the ever-escalating cycle of selection 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 manifestations of UTI).

At present, the most reliably and broadly active antimicrobial agents

in vitro against Enterobacteriaceae are the carbapenems (excepting

imipenem, to which the Proteeae [Proteus, Morganella, Providencia]

are intrinsically resistant); the aminoglycosides amikacin and plazomicin (excepting the Proteeae); the fourth-generation cephalosporin

cefepime; the β-lactamase inhibitor combination agents piperacillintazobactam, ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam; and the novel cephalosporin-siderophore

cefiderocol. A limitation of imipenem/cilastatin-relebactam; the

tetracycline derivatives tigecycline, omadacycline, and eravacycline; and the polymyxins B and E (colistin) (which are otherwise

very active) is their poor activity against the Proteeae and Serratia.

Furthermore, the tetracycline derivatives achieve suboptimal concentrations at several anatomic sites (including urine and blood).

Clinical data are limited for cefiderocol outside of UTIs; thus, caution is in order for serious infections.

The number of antimicrobial agents effective against certain

Enterobacteriaceae is shrinking, and truly pan-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 takes into account 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., prolonged infusion of β-lactam agents to maintain drug

levels above the minimal inhibitory concentration [MIC]) may

increase the chance for a successful outcome. In the near future,

point-of-care identification of resistance mechanisms in GNB 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. 177).

Although some GNB are more pathogenic than others, it is usually

prudent, if possible, to design an antimicrobial regimen active

against all of 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.

ANTIMICROBIAL TREATMENT AND RESISTANCE

MECHANISMS

The most common resistance mechanisms possessed by Enterobacteriaceae are summarized in Table 161-2. However, enzymatic

hydrolysis (e.g., β-lactamases, of which >3000 variants have been

described) and modification of antimicrobials are the major

1264 PART 5 Infectious Diseases

mediators of resistance in GNB and will be discussed in detail

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 penicillins and first-generation cephalosporins and are frequently expressed

in enteric GNB. These enzymes are inhibited by β-lactamase inhibitors (e.g., clavulanate, sulbactam, tazobactam, avibactam). 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,

aztreonam, and (in some instances) fourth-generation cephalosporins, in addition to the drugs hydrolyzed by broad-spectrum

β-lactamases. GNB that express ESBLs may also exhibit porin

mutations that result in decreased uptake of relevant β-lactam

agents (cephalosporins, β-lactam/β-lactamase inhibitor combinations, 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 (conjugal) plasmids, 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 Enterobacteriaceae. 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 ESBLproducing Enterobacteriaceae has increased worldwide, including

in the United States.

Carbapenems are the most reliably active β-lactam agents against

ESBL-expressing strains. Piperacillin-tazobactam, when active in

vitro, has been used as a carbapenem-sparing alternative, but recent

TABLE 161-2 Common Antimicrobial Resistance Mechanisms

Possessed by the Enterobacteriaceae

MECHANISM

ANTIMICROBIALS

MOST SIGNIFICANTLY

AFFECTED

COMMON MEDIATORS OF

RESISTANCE

Efflux Tetracyclines,

fluoroquinolones (FQ)

Efflux pumps

Decreased

permeability

Fosfomycin Alterations in uptake system

Target site

alteration or

over-production

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., serine

based KPC, SME, OXA; and

metallo-based NDM, VIM, IMP)

Enzymatic

modification of

antimicrobials

Aminoglycosides AAC, ANT, APH

Abbreviations: AAC, N-acetyltransferases; ANT, O-adenyltranferases; 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; SME, Serratia marcescens enzyme; TEM,

temoniera β-lactamase; VIM, Verona integron-mediated metallo-β-lactamase.

data from the MERINO trial do not support its use for bloodstream

infections. Ceftazidime-avibactam, ceftolozane-tazobactam (less

active against Klebsiella, Enterobacter, and Citrobacter), meropenemvaborbactam, imipenem/cilastatin-relebactam, and plazomicin are

active against most ESBL-producing strains and have limited clinical data that support potential utility. The roles for tigecycline,

eravacycline, and omadacycline are unclear despite these agents’

excellent in vitro activity against most Enterobacteriaceae; however,

they are inactive against Proteus, Morganella, Providencia, and

Serratia.

Oral options for the treatment of ESBL-expressing strains are

limited. Fosfomycin, nitrofurantoin (for E. coli, 75–90% susceptible), pivmecillinam (not available in the United States), and omadacycline are the most reliably active agents. Older tetracyclines (e.g.,

doxycycline and minocycline) are also 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).

The genes encoding 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 during 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 members of the Enterobacteriaceae family (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 Enterobacteriaceae have acquired plasmids

that contain AmpC β-lactamase genes.

For AmpC-expressing 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 presence of an ESBL can be excluded (a task that currently exceeds the capability of most clinical microbiology laboratories) and source control is achieved. Vaborbactam and avibactam

are the most potent β-lactamase inhibitors. Ceftazidime-avibactam,

imipenem/cilastatin-relebactam, 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, TMP-SMX, and aminoglycosides. Tigecycline, eravacycline, and

omadacycline are active in vitro (except against Proteus, Morganella,

Providencia, and Serratia).

Carbapenemases of Ambler class A (serine-based hydrolytic mechanism; K. pneumoniae carbapenemase [KPC], Serratia marcescens enzyme [SME]) and class B (metallo [zinc]-based

hydrolytic mechanism; New Delhi metallo-β-lactamase [NDM],

Verona integron-mediated metallo-β-lactamase [VIM], active on

imipenem [IMP]) confer resistance to the same drugs as do ESBLs,

plus to cephamycins and carbapenems. By contrast, Ambler class

D carbapenemases (serine-based hydrolytic mechanism, e.g., oxacillinase [OXA]) 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) is also important. 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 may

facilitate spread.

1265CHAPTER 161 Diseases Caused by Gram-Negative Enteric Bacilli

Carbapenemase production by Enterobacteriaceae (CPE) is most

prevalent in K. pneumoniae, followed by Enterobacter spp. and E.

coli, but has been described in nearly all members of the family.

M. morganii, Proteus, and Providencia exhibit intrinsic low-level

imipenem resistance. Although for carbapenem-resistant isolates

the Clinical and Laboratory Standards Institute (CLSI) no longer

recommends routine identification of CPE, such data conceivably

could inform epidemiologic surveillance, infection control efforts,

antimicrobial stewardship, and treatment decisions, especially if

susceptibility data for selected agents are not available. Genotypic

and phenotypic methods can detect carbapenemase genes or activity. Each of these methodologies has pros and cons. At the time of

this writing, CLSI endorses the modified carbapenem inactivation

method and the Carba NP test.

For the treatment of infections due to Enterobacteriaceae that

produce class A or D carbapenemases (serine-based hydrolysis;

KPC, OXA, SME), ceftazidime-avibactam is emerging as a firstline 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.

Polymyxins are also active. Clinical success against KPC-producing

CRE has also been reported for meropenem-vaborbactam and, to

a lesser extent, imipenem/cilastatin-relebactam; importantly, however, neither of these agents is active against OXA-producing CRE.

For SME, based on limited in vitro data, vaborbactam is most active,

followed by avibactam, whereas relebactam is significantly less

active; this suggests that meropenem-vaborbactam or ceftazidimeavibactam should be viable treatment options for SME-producing

CRE. Ceftazidime, cefepime, and aztreonam are active against

OXA-48-like–producing CRE.

Treatment of infections due to class B metallo-β-lactamase–

producing CRE is more challenging. The polymyxins B and E currently constitute one of the last lines of defense against strains that

produce metallo-carbapenemases (e.g., NDM-1). However, these

agents’ nephrotoxicity and neurotoxicity potential, their limited

clinical efficacy, and the recent emergence of the polymyxin

resistance gene mcr-1 on a stable transferable plasmid and mcr-1–

independent resistance threaten their utility.

Aztreonam is active against metallo-carbapenemases but is

hydrolyzed by ESBLs and AmpC β-lactamases, which often coexist in XDR strains. Ongoing studies are assessing aztreonam plus

avibactam, a promising combination with in vitro activity against

class A, B, and D enzymes, for the treatment of CRE strains

that produce both NDM plus KPC or OXA. 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.

Although tigecycline, eravacycline, and omadacycline are active in

vitro, pharmacokinetic-pharmacodynamic limitations exist, and along

with the polymyxins, they exhibit poor activity against the Proteeae

and Serratia. Cefiderocol is active in vitro against KPC, most NDM

carbapenemases, and OXA (i.e., classes A, B, and D enzymes); clinical trials for the treatment of carbapenemase-resistant GNB are in

progress. Aminoglycosides, of which plazomicin is most active, 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, resistance may develop with monotherapy, and a parenteral

formulation is not yet available in the United States and certain other

countries. Collectively, these considerations recommend fosfomycin as

a second-line agent and for use in combination therapy, except perhaps

for prostatitis due to superior penetration.

Carbapenem resistance in the absence of carbapenemases can

occur in the presence of ESBLs or AmpC β-lactamases 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 antimicrobial classes is less, but data are limited on the optimal management approach for non-CP-CRE.

β-Lactamase inhibitor resistance is an uncommon (4% of E. coli/K.

pneumoniae blood isolates) but increasingly recognized phenotype

that is characterized by resistance to β-lactamase inhibitors, but

not to third-generation cephalosporins. This mechanism of resistance is distinct from production of ESBLs, AmpC β-lactamases,

and carbapenemases, and is still being delineated. Limited evidence

suggests that ceftriaxone is an appropriate treatment option for

such strains.

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. Fluoroquinolone 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 resistant to fluoroquinolones. At present, fluoroquinolones should be

considered unreliable as empirical therapy for GNB infections in

critically ill patients.

Aminoglycoside resistance in Enterobacteriaceae is conferred via

enzymatic modification by N-acetyltransferases, O-adenyltransferases,

or O-phosphotransferases, which in turn affects ribosomal binding.

Amikacin is less affected by these transferases than gentamicin and

tobramycin and therefore is generally more active. Plazomicin is

unaffected by all of these enzymes that confer resistance to amikacin, gentamicin, and tobramycin, thereby making this an important

alternative agent in the treatment of selected XDR strains (excepting the Proteeae, against which plazomicin is poorly active). An

as yet uncommon resistance mechanism involves 16S ribosomal

RNA methylases, which prevent all aminoglycosides (including

plazomicin) from binding to their target ribosomes. To date, these

methylases are most common in strains that possess metallocarbapenemases (e.g., NDM).

■ PREVENTION

(See also Chap. 142) 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 handhygiene 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.

Multi-use medication vials should be avoided if possible. Oral application of chlorhexidine decreases the incidence of pneumonia among

patients on ventilators. Increasing data support the implementation of

universal decolonization (e.g., chlorhexidine bathing) to prevent infection in ICU patients. The public health threat from CRE has resulted in

additional recommendations, especially for carbapenemase-producing

CRE, which are an even greater concern. These recommendations

include contact precautions 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 may also be appropriate.

ESCHERICHIA COLI INFECTIONS

All E. coli strains share a core genome of ~2000 genes. In contrast,

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 composition

of the E. coli accessory genome is continuously in flux, as demonstrated

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