1291CHAPTER 165 Salmonellosis

■ BURKHOLDERIA MALLEI

B. mallei causes the equine disease glanders in Africa, Asia, and South

America. The organism was eradicated from Europe and North America

decades ago. The last case seen in the United States occurred in 2001

in a laboratory worker; before that, B. mallei had last been seen in this

country in 1949. In contrast to the other organisms discussed in this

chapter, B. mallei is not an environmental organism and does not persist

outside its equine hosts. Consequently, B. mallei infection is an occupational risk for handlers of horses, equine butchers, and veterinarians

in areas of the world where it still exists. The polysaccharide capsule is

a critical virulence determinant; diabetics are thought to be especially

susceptible to infection by this organism. The organism is transmitted

from animals to humans by inoculation into the skin, where it causes

local infection with nodules and lymphadenitis. Regional lymphadenopathy is common. Respiratory secretions from infected horses

are extremely infectious. Inhalation results in clinical signs of typical

pneumonia but may also cause an acute febrile illness with ulceration

of the trachea. The organism may disseminate from the skin or lungs to

cause septicemia with signs of sepsis. The septicemic form is frequently

associated with shock and a high mortality rate. The infection may also

enter a chronic phase and present as disseminated abscesses. B. mallei

infection may present as early as 1–2 days after inhalation or (in cutaneous disease) may not become evident for months.

TREATMENT

B. mallei Infections

The antibiotic susceptibility pattern of B. mallei is similar to that of

B. pseudomallei; in addition, the organism is susceptible to the macrolides azithromycin and clarithromycin. B. mallei infection should be

treated with the same drugs and for the same duration as melioidosis.

STENOTROPHOMONAS MALTOPHILIA

S. maltophilia is the only potential human pathogen among a genus

of ubiquitous organisms found in the rhizosphere (i.e., the soil that

surrounds the roots of plants). The organism is an opportunist that

is acquired from the environment but is even more limited than P.

aeruginosa in its ability to colonize patients or cause infections. Immunocompromise is not sufficient to permit these events; rather, major

perturbations of the human flora are usually necessary for the establishment of S. maltophilia. Accordingly, most cases of human infection

occur in the setting of very broad-spectrum antibiotic therapy with

agents such as advanced cephalosporins and carbapenems, which eradicate the normal flora and other pathogens. The remarkable ability of

S. maltophilia to resist virtually all classes of antibiotics is attributable

to the possession of antibiotic efflux pumps and of two β-lactamases

(L1 and L2) that mediate β-lactam resistance, including that to carbapenems. It is fortunate that the virulence of S. maltophilia appears to be

limited. Although a serine protease is present in some strains, virulence

is probably a result of the host’s inflammatory response to components

of the organism such as LPS and flagellin. S. maltophilia is most commonly found in the respiratory tract of ventilated patients, where the

distinction between its roles as a colonizer and as a pathogen is often

difficult to make. However, S. maltophilia does cause pneumonia and

bacteremia in such patients, and these infections have led to septic

shock. Also common is central venous line–associated infection (with

or without bacteremia), which has been reported most often in patients

with cancer. S. maltophilia is a rare cause of ecthyma gangrenosum in

neutropenic patients. It has been isolated from ~5% of CF patients but

is not believed to be a significant pathogen in this setting.

TREATMENT

S. maltophilia Infections

The intrinsic resistance of S. maltophilia to most antibiotics renders

infection difficult to treat. The antibiotics to which it is most often

(although not uniformly) susceptible are TMP-SMX, ticarcillin/

clavulanate, levofloxacin, and tigecycline (Table 164-2). Consequently, a combination of TMP-SMX and ticarcillin/clavulanate

is recommended for initial therapy pending susceptibility testing.

Catheters must be removed in the treatment of bacteremia. The

treatment of VAP due to S. maltophilia is much more difficult than

that of bacteremia, with frequent development of resistance during

therapy. The newest β-lactam/β-lactamase inhibitor combinations

show mixed results against this organism.

■ FURTHER READING

Bauer KA et al: Extended-infusion cefepime reduces mortality in

patients with Pseudomonas aeruginosa infections. Antimicrob Agents

Chemother 57:2907, 2013.

Bowers DR et al: Outcomes of appropriate empiric combination

versus monotherapy for Pseudomonas aeruginosa bacteremia. Antimicrob Agents Chemother 157:1270, 2013.

Brooke JS: Stenotrophomonas maltophilia: An emerging global opportunistic pathogen. Clin Microbiol Rev 25:2, 2012.

Cattaneo C et al: P. aeruginosa bloodstream infections among hematological patients: An old or new question? Ann Hematol 91:1299,

2012.

Chuang C-H et al: Shanghai fever: A distinct Pseudomonas aeruginosa

enteric disease. Gut 63:736, 2014.

Fabre V et al: Antibiotic therapy for Pseudomonas aeruginosa bloodstream infections: How long is long enough? Clin Infect Dis 69:2011,

2019.

Horcajada JP et al: Epidemiology and treatment of multidrugresistant and extensively drug-resistant Pseudomonas aeruginosa

infections. Clin Microbiol Rev 32:e00031, 2019.

Kalil AC et al: Executive summary: Management of adults with

hospital-acquired and ventilator-associated pneumonia: 2016 clinical

practice guidelines by the Infectious Diseases Society of America and

the American Thoracic Society. Clin Infect Dis 63:575, 2016.

Peña C et al: Influence of virulence genotype and resistance profile

in the mortality of Pseudomonas aeruginosa bloodstream infections.

Clin Infect Dis 60:539, 2015.

Van Zandt KE et al: Glanders: An overview of infections in humans.

Orphanet J Rare Dis 8:131, 2013.

Wunderlink RG et al: Cefiderocol versus high-dose, extendedinfusion meropenem for the treatment of Gram-negative nosocomial

pneumonia (APEKS-NP): A randomized, double-blind, phase 3, noninferiority trial. Lancet Infect Dis 21:213, 2021.

Bacteria of the genus Salmonella are highly adapted for growth in both

humans and animals and cause a wide spectrum of disease. The growth

of serotypes Salmonella Typhi and Salmonella Paratyphi is restricted

to human hosts, in whom these organisms cause enteric (typhoid)

fever. The remaining serotypes (nontyphoidal Salmonella, or NTS) can

colonize the gastrointestinal tracts of a broad range of animals, including mammals, reptiles, birds, and insects. More than 200 serotypes

of Salmonella are pathogenic to humans, in whom they often cause

gastroenteritis and can be associated with localized infections and/or

bacteremia.

■ ETIOLOGY

This large genus of gram-negative bacilli within the family Enterobacteriaceae consists of two species: Salmonella enterica, which contains

six subspecies, and Salmonella bongori. S. enterica subspecies I includes

almost all the serotypes pathogenic for humans. Members of the seven

165 Salmonellosis

David A. Pegues, Samuel I. Miller

1292 PART 5 Infectious Diseases

Salmonella subspecies are classified into >2500 serotypes (serovars); for

simplicity, Salmonella serotypes (most of which are named for the city

where they were identified) are often used as the species designation.

For example, the full taxonomic designation S. enterica subspecies

enterica serotype Typhimurium can be shortened to Salmonella serotype Typhimurium or simply S. Typhimurium. Serotyping is based

on antigenically diverse surface structures: the somatic O antigen

(lipopolysaccharide cell-wall components), the surface Vi antigen

(restricted to S. Typhi and S. Paratyphi C), and the flagellar H antigen.

Salmonellae are gram-negative, non-spore-forming, facultatively

anaerobic bacilli that measure 2–3 μm by 0.4–0.6 μm. The initial

identification of salmonellae in the clinical microbiology laboratory is

based on growth characteristics. Salmonellae, like other Enterobacteriaceae, produce acid on glucose fermentation, reduce nitrates, and do

not produce cytochrome oxidase. In addition, all salmonellae except

Salmonella Gallinarum-Pullorum are motile by means of peritrichous

flagella, and all but S. Typhi produce gas (H2

S) on sugar fermentation.

Notably, only 1% of clinical isolates ferment lactose; a high level of

suspicion must be maintained to detect these rare clinical lactosefermenting isolates.

Although serotyping of all surface antigens can be used for formal

identification, most laboratories perform a few simple agglutination

reactions that define specific O-antigen serogroups, designated A,

B, C1

, C2

, D, and E. Strains in these six serogroups cause ~99% of

Salmonella infections in humans and other warm-blooded animals.

Molecular typing methods, including pulsed-field gel electrophoresis,

multiple-locus variable-number tandem repeat analysis, and wholegenome sequencing, are used in epidemiologic investigations to differentiate Salmonella strains of a common serotype.

■ PATHOGENESIS

All Salmonella infections begin with ingestion of organisms, most commonly in contaminated food or water. The infectious dose ranges from

200 colony-forming units (CFU) to 106

 CFU, and the ingested dose is

an important determinant of incubation period and disease severity.

Conditions that decrease either stomach acidity (an age of <1 year, acid

suppression therapy, or achlorhydric disease) or intestinal integrity

(inflammatory bowel disease, cytotoxic chemotherapy, prior gastrointestinal surgery, or alteration of the intestinal microbiome by antibiotic

administration) increase susceptibility to Salmonella infection.

Once S. Typhi and S. Paratyphi reach the small intestine, they penetrate the mucus layer of the gut and traverse the intestinal layer through

phagocytic microfold (M) cells that reside within Peyer’s patches. Salmonellae can trigger the formation of membrane ruffles in normally

nonphagocytic epithelial cells. These ruffles reach out and enclose

adherent bacteria within large vesicles by bacterium-mediated endocytosis. This process is dependent on the direct delivery of Salmonella

proteins into the cytoplasm of epithelial cells by the specialized bacterial type III secretion system. These bacterial proteins mediate alterations in the actin cytoskeleton that are required for Salmonella uptake.

After crossing the epithelial layer of the small intestine, S. Typhi

and S. Paratyphi, which cause enteric (typhoid) fever, are phagocytosed by macrophages. These salmonellae survive the antimicrobial

environment of the macrophage by sensing environmental signals that

trigger alterations in regulatory systems of the phagocytosed bacteria.

For example, PhoP/PhoQ (the best-characterized regulatory system)

triggers the alteration of the outer membrane by increasing the synthesis and transport of different outer-membrane proteins, lipopolysaccharides, and glycerophospholipids, so that the altered bacterial

surface can resist microbicidal activities and potentially alter host cell

signaling. In addition, salmonellae encode a second type III secretion

system that directly delivers bacterial proteins across the phagosome

membrane into the macrophage cytoplasm. This secretion system

functions to remodel the Salmonella-containing vacuole, promoting

bacterial survival and replication.

Once phagocytosed, typhoidal salmonellae disseminate throughout

the body in macrophages via the lymphatics and colonize reticuloendothelial tissues (liver, spleen, lymph nodes, and bone marrow). Patients

have relatively few or no signs and symptoms during this initial

incubation stage. Signs and symptoms, including fever and abdominal

pain, probably result from secretion of cytokines by macrophages and

epithelial cells in response to bacterial products that are recognized by

innate immune receptors when a critical number of organisms have

replicated. Over time, the development of hepatosplenomegaly is likely

to be related to the recruitment of mononuclear cells and the development of a specific acquired cell-mediated immune response to S. Typhi

colonization. The recruitment of additional mononuclear cells and

lymphocytes to Peyer’s patches during the several weeks after initial

colonization/infection can result in marked enlargement and necrosis

of the Peyer’s patches, which may be mediated by bacterial products

that promote cell death as well as the inflammatory response. In the

case of S. Typhi, many strains produce a toxin, which probably contributes to systemic symptoms as well as the unusual neuropsychiatric

states that can be seen in severe typhoidal illness.

In contrast to enteric fever, which is characterized by an infiltration

of mononuclear cells into the small-bowel mucosa, NTS gastroenteritis

is characterized by massive polymorphonuclear leukocyte infiltration

into both the large- and small-bowel mucosa. This response appears

to depend on the induction of interleukin 8, a strong neutrophil chemotactic factor, which is secreted by intestinal cells as a result of nontyphoidal Salmonella colonization and translocation of bacterial proteins

into host cell cytoplasm. The degranulation and release of toxic substances by neutrophils may result in damage to the intestinal mucosa,

causing the inflammatory diarrhea observed with nontyphoidal gastroenteritis. An additional important factor in the persistence of NTS

in the intestinal tract and the organism’s capacity to compete with

endogenous flora is the ability to utilize the sulfur-containing compound tetrathionate for metabolism in a microaerophilic environment.

In the presence of intestinal inflammation, tetrathionate is generated

from thiosulfate produced by epithelial cells through inflammatory cell

production of reactive oxygen species.

ENTERIC (TYPHOID) FEVER

Enteric (typhoid) fever is a systemic disease characterized by fever and

abdominal pain and caused by dissemination of S. Typhi or S. Paratyphi. The disease was initially called typhoid fever because of its clinical

similarity to typhus. In the early 1800s, typhoid fever was clearly

defined pathologically as a unique illness on the basis of its association

with enlarged Peyer’s patches and mesenteric lymph nodes. In 1869,

given the anatomic site of infection, the term enteric fever was proposed

as an alternative designation to distinguish typhoid fever from typhus.

However, to this day, the two designations are used interchangeably.

■ EPIDEMIOLOGY

In contrast to other Salmonella serotypes, the etiologic agents of

enteric fever—S. Typhi and S. Paratyphi serotypes A, B, and C—have

no known hosts other than humans. Most commonly, food-borne or

waterborne transmission results from fecal contamination by ill or

asymptomatic chronic carriers. Sexual transmission between male

partners has been described. Health care workers occasionally acquire

enteric fever after exposure to infected patients or during processing of

clinical specimens and cultures.

With improvements in food handling and water/sewage treatment,

enteric fever has become rare in developed nations. In 2017, worldwide there were an estimated 14.3 million cases of enteric fever with

136,000 deaths. The annual incidence is highest (>100 cases/100,000

population) in South Central and Southeast Asia; medium (10–100

cases/100,000) in the rest of Asia, Africa, Latin America, and Oceania

(excluding Australia and New Zealand); and low in other parts of the

world (Fig. 165-1). A high incidence of enteric fever correlates with

mixing of drinking water with human sewage. In endemic regions,

enteric fever is more common in poor neighborhoods in large cities

than rural areas and among young children and adolescents than

among other age groups. Risk factors include fecally contaminated

drinking water or ice, flooding, food and drinks purchased from street

vendors, raw fruits and vegetables grown in fields fertilized with sewage, ill household contacts, lack of hand washing and toilet access, and

evidence of prior Helicobacter pylori infection (an association probably

1293CHAPTER 165 Salmonellosis

High (>100/100,000/year) Medium (10–100/100,000/year) Low (<10/100,000/year)

FIGURE 165-1 Annual incidence of typhoid fever per 100,000 population. (Reproduced with permission from

JA Crump: The global burden of typhoid fever. Bull World Health Organ 82:346, 2004.)

related to chronically reduced gastric acidity). It is estimated that there

is one case of paratyphoid fever for every four cases of typhoid fever,

but the incidence of infection associated with S. Paratyphi A appears

to be increasing, especially in India; this increase may be a result of

vaccination for S. Typhi.

Multidrug-resistant (MDR) strains of S. Typhi emerged in the 1980s

in China and Southeast Asia and have since disseminated widely. These

strains contain plasmids encoding resistance to chloramphenicol,

ampicillin, and trimethoprim—antibiotics long used to treat enteric

fever. With the increased use of fluoroquinolones to treat MDR enteric

fever in the 1990s, MDR strains of S. Typhi and S. Paratyphi with

decreased susceptibility to ciprofloxacin (DSC; minimal inhibitory

concentration [MIC], ≥0.125 μg/mL) or ciprofloxacin resistance (MIC,

≥1 μg/mL) emerged on the Indian subcontinent and have spread with

human migration first to southern Asia and more recently to Eastern and Southern Africa. These strains represent clone H58, which

increasingly has been associated with clinical treatment failure of fluoroquinolones. Testing of isolates for resistance to the first-generation

quinolone nalidixic acid detects many but not all strains with reduced

susceptibility to ciprofloxacin and is no longer recommended. Since

2017, a large outbreak of plasmid-mediated ceftriaxone-resistant S.

Typhi H58 has been ongoing, centered in urban slums in Pakistan. The

outbreak predominantly has affected children aged 15 and younger and

is associated with fecally contaminated drinking water.

In 2015, there were 309 cases of typhoid fever and 71 cases of paratyphoid fever reported in the United States. Median age of patients with

typhoid fever was 23 years and paratyphoid fever 29 years. Most cases

of enteric fever were associated with international travel (78%), predominantly to Indian, Pakistan, and Bangladesh, and visiting friends

and family. Only 3% of travelers diagnosed with typhoid fever had

received S. Typhi vaccine within the previous 5 years. In 2015, 66%

of S. Typhi in the United States were DSC, and ~10% were resistant

to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole

(TMP-SMX). Infection with DSC S. Typhi was associated with travel

to the Indian subcontinent. In the United States, domestically acquired

cases of enteric fever are less often DSC or MDR compared to travelassociated cases and are most often sporadic, although outbreaks

linked to contaminated food products and previously unrecognized

chronic carriers continue to occur.

■ CLINICAL COURSE

Enteric fever is a misnomer, in that the hallmark features of this

disease—fever and abdominal pain—are variable. While fever is documented at presentation in >75% of cases, abdominal pain is reported in

only 30–40%. Thus, a high index of suspicion for this potentially fatal

systemic illness is necessary when a person presents with fever and a

history of recent travel to a developing country.

The mean incubation period for S. Typhi

is 10–14 days but ranges from 5 to 21 days,

depending on the inoculum size and the

host’s health and vaccination status. The

most prominent symptom is prolonged

fever (38.8°–40.5°C [101.8°–104.9°F]),

which can continue for up to 4 weeks if

untreated. S. Paratyphi A is thought to

cause milder disease than S. Typhi, with

predominantly gastrointestinal symptoms.

However, a prospective study of 669 consecutive cases of enteric fever in Kathmandu, Nepal, found that the infections

caused by these organisms were clinically

indistinguishable. In this series, symptoms

reported on initial medical evaluation

included headache (80%), chills (35–45%),

cough (30%), sweating (20–25%), myalgias (20%), malaise (10%), and arthralgia

(2–4%). Gastrointestinal manifestations

included anorexia (55%), abdominal pain

(30–40%), nausea (18–24%), vomiting

(18%), and diarrhea (22–28%) more commonly than constipation

(13–16%). Physical findings included coated tongue (51–56%), splenomegaly (5–6%), and abdominal tenderness (4–5%).

Early physical findings of enteric fever include rash (“rose spots”;

30%), hepatosplenomegaly (3–6%), epistaxis, and relative bradycardia

at the peak of high fever (<50%). Rose spots (Fig. 165-2; see also

Fig. A1-9) make up a faint, salmon-colored, blanching, maculopapular

rash located primarily on the trunk and chest. The rash is evident in

~30% of patients at the end of the first week and resolves without a

trace after 2–5 days. Patients can have two or three crops of lesions, and

Salmonella can be cultured from punch biopsies of these lesions. The

faintness of the rash makes it difficult to detect in highly pigmented

patients.

Complications of typhoid fever are estimated to occur in ~27% of

hospitalized patients and correlate with a longer duration of symptoms

before hospitalization, host factors (host genetics, immunosuppression,

acid suppression therapy, previous exposure, and vaccination status),

strain virulence and inoculum, and choice of antibiotic therapy. Gastrointestinal bleeding (6%) and intestinal perforation (1%) most commonly occur in the third and fourth weeks of illness and result from

hyperplasia, ulceration, and necrosis of the ileocecal Peyer’s patches

at the initial site of Salmonella infiltration (Fig. 165-3). Both complications are life-threatening and require immediate fluid resuscitation

and surgical intervention, with broadened antibiotic coverage for

polymicrobial peritonitis (Chap. 132) and treatment of gastrointestinal

hemorrhages, including bowel resection. Neurologic manifestations

FIGURE 165-2 “Rose spots,” the rash of enteric fever due to Salmonella Typhi or

Salmonella Paratyphi.

1294 PART 5 Infectious Diseases

occur in 2–40% of patients and include meningitis, Guillain-Barré

syndrome, neuritis, and neuropsychiatric symptoms (described as

“muttering delirium” or “coma vigil”), with picking at bedclothes or

imaginary objects.

Uncommon complications whose incidences are reduced by

prompt antibiotic treatment include disseminated intravascular coagulation, hematophagocytic syndrome, pancreatitis, hepatic and splenic

abscesses and granulomas, endocarditis, pericarditis, myocarditis,

orchitis, hepatitis, glomerulonephritis, pyelonephritis and hemolyticuremic syndrome, severe pneumonia, arthritis, osteomyelitis, endophthalmitis, and parotitis. Up to 10% of patients develop mild relapse,

usually within 2–3 weeks of fever resolution and in association with the

same strain type and susceptibility profile.

Up to 10% of untreated patients with typhoid fever excrete S. Typhi in

the feces for up to 3 months, and 2–5% develop chronic asymptomatic

carriage, shedding S. Typhi in either urine or stool for >1 year. Chronic

carriage is more common among women, infants, and persons who have

biliary abnormalities or concurrent bladder infection with Schistosoma

haematobium. S. Typhi and other salmonellae are adapted to survive

in the gallbladder environment by forming biofilms on gallstones and

invading gallbladder epithelial cells. Chronic carriage is associated with

an increased risk of gallbladder cancer, which is much more common

in locales where S. Typhi is common, such as the Indian subcontinent.

■ DIAGNOSIS

Because the clinical presentation of enteric fever is relatively nonspecific, the diagnosis needs to be considered in any febrile traveler

returning from a developing region, especially the Indian subcontinent, the Philippines, or Latin America. Other diagnoses that should

be considered in these travelers include malaria, hepatitis, bacterial

enteritis, dengue fever, rickettsial infections, leptospirosis, amebic liver

abscesses, and acute HIV infection (Chap. 124). Other than a positive

culture, no specific laboratory test is diagnostic for enteric fever. In

15–25% of cases, leukopenia and neutropenia are detectable. Leukocytosis is more common among children, during the first 10 days of

illness, and in cases complicated by intestinal perforation or secondary

infection. Other nonspecific laboratory findings include moderately

elevated values in liver function tests and muscle enzyme levels.

The definitive diagnosis of enteric fever requires the isolation of

S. Typhi or S. Paratyphi from blood, bone marrow, other sterile sites,

rose spots, stool, or intestinal secretions. The diagnostic sensitivity of

blood culture is only ~60% and is lower with low blood sample volume

and among patients with prior antimicrobial use or in the first week

of illness, reflecting the small number of S. Typhi organisms (i.e.,

<15/mL) typically present in the blood. Because almost all S. Typhi

organisms in blood are associated with the mononuclear cell/platelet

fraction, centrifugation of blood and culture of the buffy coat can

substantially reduce the time to isolation of the organism but do not

increase sensitivity.

Bone marrow culture is >80% sensitive, and, unlike that of blood

culture, its yield is not reduced by up to 5 days of prior antibiotic therapy. Culture of intestinal secretions (best obtained by a noninvasive

duodenal string test) can be positive despite a negative bone marrow

culture. If blood, bone marrow, and intestinal secretions are all cultured, the yield is >90%. Stool cultures, although negative in 60–70% of

cases during the first week, can become positive during the third week

of infection in untreated patients.

The classic Widal serologic test for “febrile agglutinins” is simple

and rapid but has limited sensitivity and specificity, especially in

endemic regions because of inability to differentiate active from prior

infection or vaccination. Other rapid serologic tests, including IDL

Tubex and Typhidot, have greater accuracy than the Widal test, but

cost has limited their routine use in developing countries. Nucleic

acid–based identification methods are not yet commercially available.

TREATMENT

Enteric (Typhoid) Fever

Enteric fever is associated with an overall case–fatality rate of

2.5%, and it rises to 4.5% among hospitalized patients. Prompt

administration of appropriate antibiotic therapy prevents severe

complications of enteric fever and reduces mortality to <1%. The

initial choice of antibiotics depends on the susceptibility of the S.

Typhi and S. Paratyphi strains in the area of residence or travel

(Table 165-1). For treatment of drug-susceptible typhoid fever,

FIGURE 165-3 Typical ileal perforation associated with Salmonella Typhi infection.

(From JM Saxe, R Cropsey: Is operative management effective in treatment of

perforated typhoid? Am J Surg 189:342, 2005.)

TABLE 165-1 Antibiotic Therapy for Enteric Fever in Adults

INDICATION AGENT DOSAGE (ROUTE) DURATION, DAYS

Empirical Treatment

Ceftriaxonea 2 g/d (IV) 10–14

Azithromycinb 1 g/d (PO) 5

Fully Susceptible

Optimal treatment Ciprofloxacinc 500 mg bid (PO) or

400 mg q12h (IV)

5–7

Azithromycin 1 g/d (PO) 5

Alternative

treatment

Amoxicillin 1 g tid (PO) or 2 g

q6h (IV)

14

Chloramphenicol 25 mg/kg tid (PO

or IV)

14–21

Trimethoprimsulfamethoxazole

160/800 mg bid

(PO)

7–14

Multidrug-Resistant, Fluoroquinolone-Susceptible

Optimal treatment Ceftriaxonea 2 g/d (IV) 10–14

Azithromycin 1 g/d (PO) 5

Alternative

treatment

Ciprofloxacin 500 mg bid (PO) or

400 mg q12h (IV)

5–14

Fluroquinolone-Resistant

Optimal treatment Ceftriaxone 2 g/d (IV) 10–14

Azithromycin 1 g/d (PO) 5

Ceftriaxone-Resistant

Optimal treatment Meropenemd

Azithromycin

1 g q8h (IV)

1 g/d (PO)

10–14

5

Eradication of Carriage

Optimal treatment Ciprofloxacin 500–750 mg bid

(PO)

28

Alternative

treatment

Amoxicilline 2 g tid (PO) 28–42

a

Or another third-generation cephalosporin (e.g., cefotaxime, 2 g q8h IV; or cefixime,

400 mg bid PO). b

Or 1 g on day 1 followed by 500 mg/d PO for 6 days. c

Or ofloxacin,

400 mg bid PO for 2–5 days. d

Or imipenem 500 mg q6h IV. e

If fluroquinolone resistant

and ampicillin susceptible.

1295CHAPTER 165 Salmonellosis

fluoroquinolones are the most effective class of agents, with cure

rates of ~98% and relapse and fecal carriage rates of <2%. Experience

is most extensive with ciprofloxacin. Short-course ofloxacin therapy is similarly successful against infection caused by quinolonesusceptible strains. However, because of the high prevalence of

strains of S. Typhi and S. Paratyphi with decreased susceptibility

to ciprofloxacin (MIC >0.125 μg/mL) on the Indian subcontinent,

in Nepal, and in some locales in Africa, fluoroquinolones should

no longer be used for empirical treatment of enteric fever in these

regions. Patients infected with DSC strains of S. Typhi or S. Paratyphi should be treated with ceftriaxone or azithromycin. Patients

with concern for ceftriaxone-resistant S. Typhi infection should be

treated empirically with a carbapenem.

Ceftriaxone, cefotaxime, and (oral) cefixime are effective for

treatment of MDR enteric fever, including that caused by DSC

and fluoroquinolone-resistant strains. These agents clear fever in

~1 week, with failure rates of ~5–10%, fecal carriage rates of <3%,

and relapse rates of 3–6%. Oral azithromycin results in defervescence

in 4–6 days, with rates of relapse and convalescent stool carriage of

<3%. Against DSC strains, azithromycin is associated with lower

rates of treatment failure and shorter durations of hospitalization

than are fluoroquinolones. Despite efficient in vitro killing of Salmonella, first- and second-generation cephalosporins as well as aminoglycosides are ineffective in the treatment of clinical infections.

Most patients with uncomplicated enteric fever can be managed

at home with oral antibiotics and antipyretics. Patients with persistent vomiting, diarrhea, and/or abdominal distension should be

hospitalized and given supportive therapy as well as a parenteral

third-generation cephalosporin, a fluoroquinolone, or carbapenem

depending on the susceptibility profile. Therapy should be administered for at least 10 days or for 5 days after fever resolution.

In a randomized, prospective, double-blind study of critically ill

patients with enteric fever (i.e., those with shock and obtundation)

in Indonesia in the early 1980s, the administration of dexamethasone (an initial dose of 3 mg/kg followed by eight doses of 1 mg/kg

every 6 h) with chloramphenicol was associated with a substantially

lower mortality rate than was treatment with chloramphenicol

alone (10% vs 55%). Although this study has not been repeated in

the “post-chloramphenicol era,” severe enteric fever remains one of

the few indications for glucocorticoid treatment of an acute bacterial infection.

The 2–5% of patients who develop chronic carriage of Salmonella

can be treated for 4 weeks with oral ciprofloxacin or other fluoroquinolones, with an eradication rate of ~80%. Oral amoxicillin is

associated with lower eradication rates than fluoroquinolones but

can be considered in persons with fluoroquinolone-resistant strains

that are susceptible to ampicillin. In cases of anatomic abnormality

(e.g., biliary or kidney stones), eradication often requires both antibiotic therapy and surgical correction.

■ PREVENTION AND CONTROL

Theoretically, it is possible to eliminate the salmonellae that cause

enteric fever because they survive only in human hosts and are spread

by contaminated food and water. However, given the high prevalence

of the disease in developing countries that lack adequate sewage

disposal and water treatment, this goal is currently unrealistic. Thus,

travelers to developing countries should be advised to monitor their

food and water intake carefully and to strongly consider immunization

against S. Typhi.

Two typhoid vaccines are commercially available in the United

States: (1) Ty21a, an oral live attenuated S. Typhi vaccine (given on

days 1, 3, 5, and 7, with revaccination with a full four-dose series every

5 years); in January 2021, manufacture of Ty21a was suspended due to

COVID-19-related reductions in international travel; and (2) Vi CPS,

a parenteral vaccine consisting of purified Vi polysaccharide from the

bacterial capsule (given in a single dose, with a booster every 2 years).

The minimal age for vaccination is 6 years for Ty21a and 2 years for

Vi CPS. In a recent meta-analysis of 18 randomized clinical trials of

vaccines for preventing typhoid fever in populations in endemic areas,

the cumulative efficacy was 50% for Ty21a at 2.5 to 3 years and 55% for

Vi CPS at 3 years. Although data on typhoid vaccines in travelers are

limited, recent evidence suggests that typhoid vaccines are moderate

effective (80%) in U.S. travelers. Currently, there is no licensed vaccine

for paratyphoid fever.

Vi CPS typhoid vaccine is poorly immunogenic in children <5 years

of age because of T cell–independent properties. In contrast, in a 2001

study, a prototype conjugated typhoid vaccine Vi-rEPA (Vi antigen

conjugated to Pseudomonas aeruginosa exotoxin A) had 91% efficacy

at 27 months in preventing typhoid fever in Vietnamese children

2−5 years of age. This vaccine is not commercially available. In a 2019

randomized clinical trial, a Vi polysaccharide–tetanus toxoid conjugate

vaccine (Vi-TT) reduced the incidence of blood culture–confirmed

typhoid fever by 82% compared to a control meningococcal vaccine

among 6-month-old to 16-year-old children in Nepal. Seroconversion

was 99% after Vi-TT vaccination. The World Health Organization now

recommends Vi-TT administered as a single 0.5-mL dose for infants

and children from 9 months to 15 years of age in high-burden settings.

In typhoid-endemic areas, immunization with Vi-TT or Vi CPS is

recommended for HIV-infected and other immunocompromised persons. The Vi-TT vaccine is not licensed in the United States.

Typhoid vaccine is not required for international travel, but it is recommended for travelers to areas where there is a moderate to high risk

of exposure to S. Typhi, especially those who are traveling to southern

Asia and other developing regions of Asia, Africa, the Caribbean, and

Central and South America and who will be exposed to potentially

contaminated food and drink. Typhoid vaccine should be considered

even for persons planning <2 weeks of travel to high-risk areas. In

addition, clinical microbiology or research laboratory staff at risk of

occupational exposure to S. Typhi and household contacts of known

S. Typhi carriers should be vaccinated. Because the protective efficacy

of vaccine can be overcome by the high inocula that are commonly

encountered in food-borne exposures, immunization is an adjunct and

not a substitute for the avoidance of high-risk foods and beverages.

Immunization is not recommended for the management of persons

who may have been exposed in a common-source outbreak.

Enteric fever is a notifiable disease in the United States. Individual

health departments have their own guidelines for allowing ill or colonized food handlers or health care workers to return to their jobs. The

reporting system enables public health departments to identify potential source patients and to treat chronic carriers in order to prevent

further outbreaks. In addition, because 1–4% of patients with S. Typhi

infection become chronic carriers, it is important to monitor patients

(especially child-care providers and food handlers) for chronic carriage

and to treat this condition if indicated.

NONTYPHOIDAL SALMONELLOSIS

■ EPIDEMIOLOGY

Worldwide, NTS causes ~93 million enteric infections and 155,000

deaths annually. In the United States, NTS causes ~12 million illnesses

annually, and the incidence has remained relatively unchanged during

the past two decades. In 2017, the incidence of NTS infection in the

United States was 16.0 cases per 100,000 persons—the second highest

rate after Campylobacter (19.1 cases per 100,000 persons) among the

10 food-borne enteric pathogens under active surveillance. The four

most common serotypes were Enteritidis, Typhimurium, Newport, and

Javiana, which together accounted for ~40% of U.S. NTS infections.

The incidence of nontyphoidal salmonellosis is highest during the

rainy season in tropical climates and during the warmer months in

temperate climates—a pattern coinciding with the peak in food-borne

outbreaks. Rates of morbidity and mortality associated with NTS are

highest among the elderly, infants, and immunocompromised individuals, including those with hemoglobinopathies, HIV infection, or

infections that cause blockade of the reticuloendothelial system (e.g.,

bartonellosis, malaria, schistosomiasis, histoplasmosis). NTS account

for a significant majority of illnesses and hospitalizations associated

with U.S. multistate food-borne outbreaks.

1296 PART 5 Infectious Diseases

Invasive NTS disease is a major cause of global morbidity and mortality, especially in sub-Saharan Africa and Southeast Asia, causing

an estimated annual 535,00 cases and 77,500 deaths. Invasive NTS

disease is not as common as Salmonella enterocolitis but is associated

with a much higher case–fatality rate (14.5%), especially in children;

the elderly; those with poor nutrition, malaria, or HIV infection;

and in areas of low sociodemographic development. In sub-Saharan

Africa, specific endemic NTS strain types, including S. Typhimurium

sequence type (ST) 131, S. Enteritidis sequence type 11, S. Dublin, and

S. Isangi, are the predominant cause of invasive NTS disease.

Unlike S. Typhi and S. Paratyphi, whose only reservoir is humans,

NTS can be acquired from multiple animal and plant reservoirs that

are part of the typical food supply. Transmission is most commonly

associated with food products of animal origin (especially eggs, poultry, undercooked ground meat, and dairy products), fresh produce

contaminated with animal waste, and contact with animals or their

environments. In the United States, NTS are the second most common

cause of food-borne outbreaks after norovirus, causing 30% of outbreaks and 35% of outbreak-associated illnesses.

S. Enteritidis infection associated with chicken eggs emerged as

a major cause of food-borne disease during the 1980s and 1990s. S.

Enteritidis infection of the ovaries and upper oviduct tissue of hens

results in contamination of egg contents before shell deposition. Infection is spread to egg-laying hens from breeding flocks and through

contact with rodents and manure. The number of S. Enteritidis

outbreaks and the proportion attributable to egg-containing foods

have continued to decline since the mid-1990s; these declines have

coincided with interventions in the egg-producing and food service

industries. Despite these control efforts, outbreaks of S. Enteritidis

infection associated with shell eggs continue to occur. In 2010, a

national outbreak of S. Enteritidis infection resulted in >1900 reported

illnesses and the recall of 500 million eggs. Transmission via contaminated eggs can be prevented by cooking eggs until the yolk is solidified

and pasteurizing egg products.

Salmonella serotype 4,[5],12:i:-, an antigenic variant of S. Typhimurium that lacks the second stage flagellar antigen, has dramatically

emerged as a foodborne pathogen associated with pigs and pork products. This serotype is now the second most common NTS in Europe

and the fifth most common in the United States. These strains are multidrug resistant; in addition to resistance to ampicillin, streptomycin,

sulfonamides, and tetracycline, strains from the United States also have

phenotypic resistance to the veterinary antimicrobials enrofloxacin

and cefdinir, which are widely used in pork production.

Centralization of food processing and widespread food distribution

have contributed to the increased incidence of NTS in developed

countries. NTS account for a significant majority of illnesses and

hospitalizations associated with multistate foodborne outbreaks in the

United States. Manufactured foods to which recent multistate Salmonella outbreaks have been traced include peanut butter; milk products,

including infant formula; and various processed foods, including packaged breakfast cereal, salsa, frozen prepared meals, and snack foods.

Large outbreaks also have been linked to fresh produce, including

alfalfa sprouts, nuts/seeds, cantaloupe, mangoes, papayas, tomatoes,

and raw meal replacement powder; these items become contaminated

by manure or water at a single site and then are widely distributed.

An estimated 6% of sporadic Salmonella infections in the United

States are attributed to contact with reptiles or amphibians, especially

iguanas, snakes, turtles, and lizards. Other pets, including hedgehogs,

birds, rodents, baby chicks, ducklings, dogs, and cats, also are potential sources of NTS. Compared to foodborne outbreaks, outbreaks of

NTS linked to animal contact more commonly affect young children

(<1−4 years of age), result in hospitalization, and are more sustained.

Increasing antibiotic resistance in NTS species is a global problem

and has been linked to the widespread use of antimicrobial agents in

food animals and especially in animal feed. In the early 1990s, S. Typhimurium definitive phage type 104 (DT104), characterized by resistance

to at least five antibiotics (ampicillin, chloramphenicol, streptomycin,

sulfonamides, and tetracyclines; R-type ACSSuT), emerged worldwide.

In 2015, resistance to at least ACSSuT was reported in 2.7% of U.S.

NTS isolates, including 10.8% of S. Typhimurium isolates. Acquisition

is associated with exposure to ill farm animals and to various meat

products, including uncooked or undercooked ground beef. Although

probably no more virulent than susceptible S. Typhimurium strains,

DT104 strains are associated with an increased risk of bloodstream

infection and hospitalization.

Because of increased resistance to conventional antibiotics such as

ampicillin and TMP-SMX, extended-spectrum cephalosporins and fluoroquinolones have emerged as the agents of choice for the treatment

of MDR NTS infections. In 2015, 2.7% of NTS strains in the United

States were resistant to ceftriaxone. Most ceftriaxone-resistant isolates

contain plasmid-encoded AmpC β-lactamases that were probably

acquired by horizontal genetic transfer from Escherichia coli strains in

food-producing animals—an event linked to the widespread use of the

veterinary cephalosporin ceftiofur.

Since the early 2000s, strains of DSC NTS (MIC, ≥0.125 μg/mL)

have emerged and have been associated with delayed response and

treatment failure. In 2015, 5.8% of NTS isolates in the United States

were DSC. These strains have diverse resistance mechanisms, including single and multiple mutations in the DNA gyrase genes gyrA and

gyrB, mutations in the chromosomally encoded quinolone resistance–

determining region, and plasmid-encoded quinolone resistance genes

that are not reliably detected by nalidixic acid susceptibility testing or

standard ciprofloxacin disk diffusion. In 2012, the U.S. Clinical Laboratory Standards Institute proposed a lower ciprofloxacin susceptibility

breakpoint (≥0.06 μg/mL) for all Salmonella species to address this

issue. Because commercial test systems do not contain ciprofloxacin

concentrations low enough to allow use of this breakpoint, laboratories

need to determine the ciprofloxacin MIC by Etest or another alternative method.

While NTS strains with decreased susceptibility to azithromycin

(MIC, ≥32 μg/mL) remain uncommon in the United States (0.3% in

2015), in 2018–2019, there was an outbreak of 255 cases of azithromycinresistant S. Newport infection in 32 states linked to beef obtained in

the United States and soft cheese obtained in Mexico. Sporadic cases

of carbapenemase-resistant NTS have been reported in Europe, North

Africa, and southern Asia.

■ CLINICAL MANIFESTATIONS

Gastroenteritis Infection with NTS most often results in gastroenteritis indistinguishable from that caused by other enteric pathogens.

Nausea, vomiting, and diarrhea occur 6–48 h after the ingestion of

contaminated food or water. Patients often experience abdominal

cramping and fever (38–39°C [100.5–102.2°F]). Diarrheal stools are

usually loose, nonbloody, and of moderate volume. However, largevolume watery stools, bloody stools, or symptoms of dysentery may

occur. Rarely, NTS causes pseudoappendicitis or an illness that mimics

inflammatory bowel disease.

Gastroenteritis caused by NTS is usually self-limited. Diarrhea

resolves within 3–7 days and fever within 72 h. Stool cultures remain

positive for 4–5 weeks after infection and—in rare cases of chronic

carriage (<1%)—for >1 year. Persistent NTS infection and relapsing

diarrhea have been described in a small fraction of Israeli patients and

were associated with in-host single nucleotide mutations in key virulence regulators. For acute NTS gastroenteritis, antibiotic treatment

usually is not recommended and may prolong fecal carriage. Neonates,

the elderly, and immunosuppressed patients (e.g., transplant recipients, HIV-infected persons) with NTS gastroenteritis are especially

susceptible to dehydration and invasive infection and may require

hospitalization and antibiotic therapy. Acute NTS gastroenteritis was

associated with a threefold increased risk of dyspepsia and irritable

bowel syndrome at 1 year in a study from Spain.

Bacteremia and Endovascular Infections Up to 8% of patients

with NTS gastroenteritis develop bacteremia; of these, 5–10% develop

localized infections. Bacteremia and metastatic infection are most

common with Salmonella Choleraesuis and Salmonella Dublin and