Chapter 171: Salmonellosis¶

Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points¶

Enteric (typhoid) fever is caused by S. Typhi and S. Paratyphi (human-restricted), while nontyphoidal Salmonella (NTS) infects humans and animals.
Rose spots are faint, salmon-colored, blanching maculopapular rashes on the trunk/chest appearing in ~30% of typhoid patients.
Relative bradycardia (Faget sign) is a classic physical finding in enteric fever, though absent in ~50% of cases.
Intestinal perforation and GI bleeding typically occur in weeks 3-4 due to hyperplasia/ulceration of Peyer's patches.
Chronic carriage (>1 year) occurs in 2-5% of untreated patients, more common in women, infants, and those with biliary abnormalities.
MDR S. Typhi (DSC) and XDR strains (H58 clone) are prevalent in the Indian subcontinent and Pakistan, requiring empiric carbapenems or azithromycin.
Typhoid conjugate vaccines (TCV) are effective in children <2 years and recommended for high-incidence regions; unconjugated vaccines (Vi, Ty21a) are less effective in young children.
NTS is the second most common foodborne pathogen in the US (after Campylobacter), with S. Enteritidis and S. Typhimurium being the most common serotypes.
Invasive NTS (ST313) is emerging in sub-Saharan Africa and presents with nonspecific febrile illness similar to enteric fever.
Bone marrow culture is ~80% sensitive and not reduced by prior antibiotic use, unlike blood culture (~40-60% sensitivity).

📑 Table of Contents¶

1. DEFINITION & OVERVIEW
1.1 Taxonomy & Classification
1.2 Microbiology
2. EPIDEMIOLOGY
3. ETIOLOGY & PATHOPHYSIOLOGY
3.1 Enteric (Typhoid) Fever Pathogenesis
3.2 NTS Gastroenteritis Pathogenesis
4. CLINICAL FEATURES
4.1 Enteric Fever Clinical Presentation
4.2 NTS Gastroenteritis Clinical Presentation
5. DIFFERENTIAL DIAGNOSIS
6. INVESTIGATIONS & DIAGNOSIS
6.1 Diagnostic Sensitivity & Specificity
7. MANAGEMENT & TREATMENT
7.1 Antibiotic Therapy for Enteric Fever
7.2 Prevention & Control
8. PROGNOSIS & COMPLICATIONS
9. SPECIAL CONSIDERATIONS
10. KEY PEARLS & CLINICAL TRAPS
Figures & Illustrations

📋 Figures in This Chapter¶

#	Type	Description
1	🖼 Figure	Typical ileal perforation associated with Salmonella Typhi infection
2	🖼 Figure	Estimated national typhoid fever incidence and worldwide typhoid conjugate vaccine introduction, 2019–2022

1. DEFINITION & OVERVIEW¶

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.
Harrison's defines this as: 'Bacteria of the genus Salmonella are highly adapted for growth in both humans and animals and cause a wide spectrum of disease.'
Salmonellae are gram-negative, non-spore-forming, facultatively anaerobic bacilli that measure 2–3 μm by 0.4–0.6 μm.

1.1 Taxonomy & Classification¶

The 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 Salmonella subspecies are classified into >2600 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.
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.
All salmonellae except Salmonella Gallinarum-Pullorum are motile by means of peritrichous flagella.
All but S. Typhi produce gas (H2) on sugar fermentation.

1.2 Microbiology¶

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.
Notably, only 1% of clinical isolates ferment lactose; a high level of suspicion must be maintained to detect these rare clinical lactose-fermenting 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, C, D, and E.
Strains in these six serogroups cause ~99% of Salmonella infections in humans and other warm-blooded animals.
Whole-genome sequencing is used in epidemiologic investigations to identify the source of foodborne outbreaks and to explore the international transmission of multidrug-resistant Salmonella strains.

2. 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.
An estimated 9.2–21 million cases of typhoid fever, 5 million cases of paratyphoid fever, and 110,000–280,000 deaths occur each year.
The highest estimated annual incidence rates of typhoid fever are in the Indian subcontinent, including Pakistan, Bangladesh, Nepal, India, and Eastern Mediterranean and African regions.
Incidence rates exceed 1000 cases per 100,000 children in some urban areas.
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.
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) or ciprofloxacin resistance emerged on the Indian subcontinent.
These strains represent clone H58, which is increasingly associated with clinical treatment failure of fluoroquinolones.
Since emerging in 2016 in urban slums of Sindh province in Southeastern Pakistan, an extensively drug-resistant (XDR) S. Typhi H58 clone with plasmid-mediated extended-spectrum beta-lactamase (ESBL) resistance has now become the dominant cause of typhoid fever in Pakistan.
Air travel from Pakistan has facilitated the international spread of this XDR strain.
Azithromycin resistance has emerged in multiple countries where azithromycin is used for first-line treatment of enteric fever and for mass administration for trachoma.
In the United States, the Centers for Disease Control and Prevention (CDC) estimates that typhoid fever affects 5700 persons each year.
In 2015, the median age of patients with typhoid fever was 23 years, and it was 29 years for paratyphoid fever.
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 with travel-associated cases and are most often sporadic, although outbreaks linked to contaminated food products and previously unrecognized chronic carriers continue to occur.
Worldwide, NTS causes ~93–150 million enteric infections and ~60,000–155,000 deaths annually.
In the United States, the CDC estimates that NTS causes ~1.35 million illnesses, 26,500 hospitalizations, and 420 deaths each year.
In 2022, the incidence of NTS infection in the United States was 14.5 cases per 100,000 persons—the second highest rate after Campylobacter (17.4 cases per 100,000 persons) among the 8 food-borne enteric pathogens under active surveillance.
Although declining modestly since 2017, the incidence rate remains above the U.S. Healthy People 2030 goal of 11.5 cases per 100,000 persons.
Globally, S. Typhimurium and S. Enteritidis are the most common serotypes causing human disease.
The incidence of NTS infection 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).
Over the past three decades, bloodstream infection caused by invasive NTS, predominantly associated with closely related lineages of S. Typhimurium sequence type (ST) 313, as well as S. Enteritidis ST11, have emerged in sub-Saharan Africa and have spread to South Asia, the United Kingdom, and Brazil.
These invasive NTS strains are adapted more to person-to-person transmission through stepwise loss-of-function mutations and typically present with nonspecific febrile illness similar to enteric fever and uncommonly cause diarrhea.
In 2017, there were ~535,000 invasive NTS cases and ~77,500 deaths, most of which (~80%) occurred in sub-Saharan Africa.
Most (75%) S. Typhimurium ST313 isolates are MDR to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol, and some are also resistant to ceftriaxone or ciprofloxacin, especially in South Asia.
Recently, a sublineage of S. Typhimurium ST313 combining MDR with both ceftriaxone and azithromycin resistance has emerged in the Democratic Republic of the Congo.
The incidence of invasive NTS infection is highest in children <5 years of age, exceeding 100 per 100,000 person-years in several West African countries.
Risk is associated with malaria, HIV, malnutrition, and unclean drinking water sources.
Transmission from asymptomatic stool carriers in the household and food or water sources has been proposed, but the sources of invasive NTS infection remain uncertain.
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).
NTS accounts for a significant majority of illnesses and hospitalizations associated with multistate foodborne outbreaks and retail food establishment outbreaks in the United States.
Manufactured foods to which recent multistate Salmonella outbreaks have been traced include peanut butter; milk products, including powdered infant formula; and various processed foods, including packaged breakfast cereal, salsa, frozen prepared meals, and snack foods.
Large outbreaks have also been linked to fresh produce, including alfalfa sprouts, nuts/seeds, cantaloupe, mangoes, papayas, tomatoes, and the herbal substance kratom consumed for its stimulant effect.
These items become contaminated by manure or water at a single site and then are widely distributed.
In the United States, NTS infection associated with exotic pets is an ongoing clinical and public health problem, especially from contact with reptiles or amphibians, including iguanas, snakes, turtles, and lizards.
Other pets, including hedgehogs, rodents, birds, baby chicks, ducklings, dogs, and cats, also are potential sources of NTS.
Compared with 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 United States, clinically important resistant NTS infections, defined as resistance to ampicillin or ceftriaxone or nonsusceptibility to ciprofloxacin, increased an estimated 40% during 2015–2016 (annual incidence ~220,000) compared with 2004–2008 (~159,000 infections).
The incidence (51.0 per 100,000 persons per year) and proportion of invasive NTS infections that are multidrug-resistant (75% with co-resistance to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol) is dramatically higher across all sub-Saharan African regions.
In the United States, infection with NTS with any antimicrobial resistance compared with NTS with no resistance are less likely to be associated with an outbreak and more likely to be associated with international travel, an increased risk of hospitalization, hospital length of stay, and death.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

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 10^6 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.
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 because of nontyphoidal Salmonella colonization and translocation of bacterial proteins and LPS into host cell cytoplasm with subsequent activation of inflammasomes.
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.
In contrast to nontyphoidal Salmonellae, typhoidal Salmonellae do not effectively colonize the intestinal tract but have evolved as systemic pathogens, largely through gene loss and perhaps by the loss of the ability to utilize butyrate within the human intestine.
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.
Transmission via contaminated eggs can be prevented by cooking eggs until the yolk is solidified and pasteurizing egg products.
Increasingly, outbreaks of S. Enteritidis infection are associated with other foods, including meat, chicken, vegetables, dairy, and baked goods.
Salmonella serotype 4,[5],12:i:–, an antigenic variant of S. Typhimurium that lacks the second-stage flagellar antigen, has emerged since the 1990s as a foodborne pathogen primarily associated with pigs and pork products.
This serotype is the second most common NTS in Europe and the fifth most common in the United States.
These strains are MDR, with resistance to ampicillin, streptomycin, sulfonamides, and tetracycline.
Increasing reports of plasmid-mediated colistin resistance in these strains have been linked to international travel to Thailand and swine farm isolates.

3.1 Enteric (Typhoid) Fever Pathogenesis¶

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 based on 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.
The two designations are used interchangeably.

3.2 NTS Gastroenteritis Pathogenesis¶

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 because of nontyphoidal Salmonella colonization and translocation of bacterial proteins and LPS into host cell cytoplasm with subsequent activation of inflammasomes.
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.

4. CLINICAL FEATURES¶

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 most prominent symptom is prolonged fever (38.8°–40.5°C [101.8°–104.9°F]), which can continue for 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 (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.
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 because of nontyphoidal Salmonella colonization and translocation of bacterial proteins and LPS into host cell cytoplasm with subsequent activation of inflammasomes.
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.

4.1 Enteric Fever Clinical Presentation¶

The most prominent symptom is prolonged fever (38.8°–40.5°C [101.8°–104.9°F]), which can continue for 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%).

4.2 NTS Gastroenteritis Clinical Presentation¶

NTS causes ~93–150 million enteric infections and ~60,000–155,000 deaths annually worldwide.
In the United States, the CDC estimates that NTS causes ~1.35 million illnesses, 26,500 hospitalizations, and 420 deaths each year.
In 2022, the incidence of NTS infection in the United States was 14.5 cases per 100,000 persons—the second highest rate after Campylobacter (17.4 cases per 100,000 persons) among the 8 food-borne enteric pathogens under active surveillance.
Although declining modestly since 2017, the incidence rate remains above the U.S. Healthy People 2030 goal of 11.5 cases per 100,000 persons.
Globally, S. Typhimurium and S. Enteritidis are the most common serotypes causing human disease.
The incidence of NTS infection 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).
Over the past three decades, bloodstream infection caused by invasive NTS, predominantly associated with closely related lineages of S. Typhimurium sequence type (ST) 313, as well as S. Enteritidis ST11, have emerged in sub-Saharan Africa and have spread to South Asia, the United Kingdom, and Brazil.
These invasive NTS strains are adapted more to person-to-person transmission through stepwise loss-of-function mutations and typically present with nonspecific febrile illness similar to enteric fever and uncommonly cause diarrhea.
In 2017, there were ~535,000 invasive NTS cases and ~77,500 deaths, most of which (~80%) occurred in sub-Saharan Africa.
Most (75%) S. Typhimurium ST313 isolates are MDR to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol, and some are also resistant to ceftriaxone or ciprofloxacin, especially in South Asia.
Recently, a sublineage of S. Typhimurium ST313 combining MDR with both ceftriaxone and azithromycin resistance has emerged in the Democratic Republic of the Congo.
The incidence of invasive NTS infection is highest in children <5 years of age, exceeding 100 per 100,000 person-years in several West African countries, and risk is associated with malaria, HIV, malnutrition, and unclean drinking water sources.
Transmission from asymptomatic stool carriers in the household and food or water sources has been proposed, but the sources of invasive NTS infection remain uncertain.
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).
NTS accounts for a significant majority of illnesses and hospitalizations associated with multistate foodborne outbreaks and retail food establishment outbreaks in the United States.
Manufactured foods to which recent multistate Salmonella outbreaks have been traced include peanut butter; milk products, including powdered infant formula; and various processed foods, including packaged breakfast cereal, salsa, frozen prepared meals, and snack foods.
Large outbreaks have also been linked to fresh produce, including alfalfa sprouts, nuts/seeds, cantaloupe, mangoes, papayas, tomatoes, and the herbal substance kratom consumed for its stimulant effect.
These items become contaminated by manure or water at a single site and then are widely distributed.
In the United States, NTS infection associated with exotic pets is an ongoing clinical and public health problem, especially from contact with reptiles or amphibians, including iguanas, snakes, turtles, and lizards.
Other pets, including hedgehogs, rodents, birds, baby chicks, ducklings, dogs, and cats, also are potential sources of NTS.
Compared with 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.

5. DIFFERENTIAL DIAGNOSIS¶

Other diagnoses that should be considered in these travelers include malaria, viral hepatitis, bacterial enteritis, dengue fever, rickettsial infections, leptospirosis, amebic liver abscesses, and acute HIV infection.
Invasive NTS typically present with nonspecific febrile illness similar to enteric fever and uncommonly cause diarrhea.
In the United States, NTS infection associated with exotic pets is an ongoing clinical and public health problem, especially from contact with reptiles or amphibians, including iguanas, snakes, turtles, and lizards.
Other pets, including hedgehogs, rodents, birds, baby chicks, ducklings, dogs, and cats, also are potential sources of NTS.

6. INVESTIGATIONS & DIAGNOSIS¶

Because the clinical presentation of enteric fever is relatively non-specific, the diagnosis needs to be considered in any febrile traveler returning from a developing region, especially the Indian subcontinent, and the Southeast Asian or African region.
Other diagnoses that should be considered in these travelers include malaria, viral hepatitis, bacterial enteritis, dengue fever, rickettsial infections, leptospirosis, amebic liver abscesses, and acute HIV infection.
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 ~40–60% 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., 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.
Rapid immunodiagnostic commercial tests, including Tubex and Typhidot, mainly focus on detection of IgM and IgG antibodies to O and H antigens and are widely used at point of care to diagnose typhoid and paratyphoid fever because they are simple and low cost.
In a 2017 systematic review, these rapid diagnostic tests had sensitivities ranging from ~70% to 80% and specificities ranging from ~80% to 90% and thus are not sufficiently accurate to replace blood cultures as the main approach to diagnose enteric fever.
PCR detection of S. Typhi and S. Paratyphi in the blood have sensitivities of ~40–100%, depending on the gene targets.
Molecular-based test platforms were scarce in resource-limited settings, but advancements and investments in molecular diagnostics arising from the SARS-CoV-2 pandemic have made feasible the widespread use of molecular tests for diagnosis of enteric fever.
In the United States, the CDC estimates that typhoid fever affects 5700 persons each year, a number far in excess of the ~350 cases of typhoid fever and ~90 cases of paratyphoid fever reported annually.
In 2015, the median age of patients with typhoid fever was 23 years, and it was 29 years for paratyphoid fever.
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 with travel-associated cases and are most often sporadic, although outbreaks linked to contaminated food products and previously unrecognized chronic carriers continue to occur.

6.1 Diagnostic Sensitivity & Specificity¶

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 ~40–60% 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., 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.
Rapid immunodiagnostic commercial tests, including Tubex and Typhidot, mainly focus on detection of IgM and IgG antibodies to O and H antigens and are widely used at point of care to diagnose typhoid and paratyphoid fever because they are simple and low cost.
In a 2017 systematic review, these rapid diagnostic tests had sensitivities ranging from ~70% to 80% and specificities ranging from ~80% to 90% and thus are not sufficiently accurate to replace blood cultures as the main approach to diagnose enteric fever.
PCR detection of S. Typhi and S. Paratyphi in the blood have sensitivities of ~40–100%, depending on the gene targets.
Molecular-based test platforms were scarce in resource-limited settings, but advancements and investments in molecular diagnostics arising from the SARS-CoV-2 pandemic have made feasible the widespread use of molecular tests for diagnosis of enteric fever.

7. MANAGEMENT & TREATMENT¶

Enteric fever is associated with an overall case-fatality rate of 2.5%, but mortality rates rise to 4.5% among hospitalized patients and to 10–30% if untreated.
Prompt administration of appropriate antibiotic therapy prevents severe complications of enteric fever and reduces mortality to 20 years ago, and data on antimicrobial resistance could not be analyzed.
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 and in some locales in Africa, fluoroquinolones should no longer be used for empirical treatment of enteric fever in these regions.
Patients with concern for ceftriaxone-resistant S. Typhi infection based on a history of travel to Pakistan should be treated empirically with a carbapenem or azithromycin.
Ceftriaxone, cefotaxime, and (oral) cefixime are effective for treatment of MDR enteric fever in adults and children, 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%.
Fluoroquinolones are effective against susceptible strains, with cure rates of ~98% and relapse and fecal carriage rates of <2%.
Oral azithromycin is recommended for the treatment of uncomplicated enteric fever, including ESBL, DSC, and fluoroquinolone-resistant strains, and 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.
Carbapenems are increasingly being used to treat complicated XDR S. Typhi and infections, but cost and IV route of administration are significant barriers.
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.
Steroid treatment beyond 48 hours may increase the relapse rate.
The 2–5% of patients who develop chronic carriage of fluoroquinolone-susceptible S. Typhi can be treated for 4 weeks with oral ciprofloxacin or other fluoroquinolones, with an eradication rate of ~80%.
A 4-week course of oral azithromycin can potentially be used to treat carriers with fluoroquinolone-resistant strains, but clinical experience is limited.
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, kidney, or bladder stones), eradication often requires both antibiotic therapy and surgical correction.
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.
Steroid treatment beyond 48 hours may increase the relapse rate.
The 2–5% of patients who develop chronic carriage of fluoroquinolone-susceptible S. Typhi can be treated for 4 weeks with oral ciprofloxacin or other fluoroquinolones, with an eradication rate of ~80%.
A 4-week course of oral azithromycin can potentially be used to treat carriers with fluoroquinolone-resistant strains, but clinical experience is limited.
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, kidney, or bladder stones), eradication often requires both antibiotic therapy and surgical correction.
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.
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.
Transmission via contaminated eggs can be prevented by cooking eggs until the yolk is solidified and pasteurizing egg products.
Increasingly, outbreaks of S. Enteritidis infection are associated with other foods, including meat, chicken, vegetables, dairy, and baked goods.
Salmonella serotype 4,[5],12:i:–, an antigenic variant of S. Typhimurium that lacks the second-stage flagellar antigen, has emerged since the 1990s as a foodborne pathogen primarily associated with pigs and pork products.
This serotype is the second most common NTS in Europe and the fifth most common in the United States.
These strains are MDR, with resistance to ampicillin, streptomycin, sulfonamides, and tetracycline.
Increasing reports of plasmid-mediated colistin resistance in these strains have been linked to international travel to Thailand and swine farm isolates.
Centralization of food processing and widespread food distribution have contributed to the increased incidence of NTS in developed countries.
NTS accounts for a significant majority of illnesses and hospitalizations associated with multistate foodborne outbreaks and retail food establishment outbreaks in the United States.
Manufactured foods to which recent multistate Salmonella outbreaks have been traced include peanut butter; milk products, including powdered infant formula; and various processed foods, including packaged breakfast cereal, salsa, frozen prepared meals, and snack foods.
Large outbreaks have also been linked to fresh produce, including alfalfa sprouts, nuts/seeds, cantaloupe, mangoes, papayas, tomatoes, and the herbal substance kratom consumed for its stimulant effect.
These items become contaminated by manure or water at a single site and then are widely distributed.
In the United States, NTS infection associated with exotic pets is an ongoing clinical and public health problem, especially from contact with reptiles or amphibians, including iguanas, snakes, turtles, and lizards.
Other pets, including hedgehogs, rodents, birds, baby chicks, ducklings, dogs, and cats, also are potential sources of NTS.
Compared with 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 United States, clinically important resistant NTS infections, defined as resistance to ampicillin or ceftriaxone or nonsusceptibility to ciprofloxacin, increased an estimated 40% during 2015–2016 (annual incidence ~220,000) compared with 2004–2008 (~159,000 infections).
The incidence (51.0 per 100,000 persons per year) and proportion of invasive NTS infections that are multidrug-resistant (75% with co-resistance to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol) is dramatically higher across all sub-Saharan African regions.
In the United States, infection with NTS with any antimicrobial resistance compared with NTS with no resistance are less likely to be associated with an outbreak and more likely to be associated with international travel, an increased risk of hospitalization, hospital length of stay, and death.

7.1 Antibiotic Therapy for Enteric Fever¶

Enteric fever is associated with an overall case-fatality rate of 2.5%, but mortality rates rise to 4.5% among hospitalized patients and to 10–30% if untreated.
Prompt administration of appropriate antibiotic therapy prevents severe complications of enteric fever and reduces mortality to 20 years ago, and data on antimicrobial resistance could not be analyzed.
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 and in some locales in Africa, fluoroquinolones should no longer be used for empirical treatment of enteric fever in these regions.
Patients with concern for ceftriaxone-resistant S. Typhi infection based on a history of travel to Pakistan should be treated empirically with a carbapenem or azithromycin.
Ceftriaxone, cefotaxime, and (oral) cefixime are effective for treatment of MDR enteric fever in adults and children, 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%.
Fluoroquinolones are effective against susceptible strains, with cure rates of ~98% and relapse and fecal carriage rates of <2%.
Oral azithromycin is recommended for the treatment of uncomplicated enteric fever, including ESBL, DSC, and fluoroquinolone-resistant strains, and 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.
Carbapenems are increasingly being used to treat complicated XDR S. Typhi and infections, but cost and IV route of administration are significant barriers.
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.
Steroid treatment beyond 48 hours may increase the relapse rate.
The 2–5% of patients who develop chronic carriage of fluoroquinolone-susceptible S. Typhi can be treated for 4 weeks with oral ciprofloxacin or other fluoroquinolones, with an eradication rate of ~80%.
A 4-week course of oral azithromycin can potentially be used to treat carriers with fluoroquinolone-resistant strains, but clinical experience is limited.
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, kidney, or bladder stones), eradication often requires both antibiotic therapy and surgical correction.

Table 1 — TABLE 171-1 Antibiotic Therapy for Enteric Fever in Adults¶

INDICATION	AGENT	DOSAGE (ROUTE)	DURATION, DAYS
Empirical Treatment	Ceftriaxone	2 g/d (IV)	10–14
	Ciprofloxacin	500 mg bid (PO) or 400 mg q12h (IV)	5–7
	Azithromycin	1 g/d (PO)	5
Fully Susceptible	Ceftriaxone	2 g/d (IV)	10–14
	Ciprofloxacin	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
	Trimethoprim-sulfamethoxazole	160/800 mg bid (PO)	7–14
Multidrug-Resistant, Depending on the Susceptibility Pattern	Ceftriaxone	2 g/d (IV)	10–14
	Ciprofloxacin	500 mg bid (PO) or 400 mg q12h (IV)	5–7
	Azithromycin	1 g/d (PO)	5
Ceftriaxone-Resistant	Meropenem	1 g q8h (IV)	10–14
	Azithromycin	1 g q8h (IV) or 1 g/d (PO)	5
Eradication of Carriage	Ciprofloxacin	500–750 mg bid (PO)	28
	Azithromycin	500 mg (PO)	28

7.2 Prevention & 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 unconjugated 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); 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 2018 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 moderately effective (80%) in U.S. travelers.
Unconjugated typhoid vaccines are poorly immunogenic in children <5 years of age because of limited ability to elicit T cell–dependent immune responses and immunologic memory.
Compared with unconjugated vaccines, typhoid Vi polysaccharide conjugated vaccines are effective in children <2 years of age and elicit substantially longer duration of protection.
The World Health Organization has recommended two typhoid conjugate vaccines (TCV) prioritized to prevent typhoid fever in countries with high incidence rates—Typbar TCV (manufactured by Bharat Biotech) in 2018 and TYPHIBEV (manufactured by Biological E) in 2020.
A single intramuscular 0.5-mL dose of either TCV is safe and 79–95% effective, with antibody response persisting up to 7 years.
As of 2023, TCV has been routinely introduced in national immunization programs in Pakistan, Nepal, Liberia, Zimbabwe, Malawi, Samoa.
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.
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.
Transmission via contaminated eggs can be prevented by cooking eggs until the yolk is solidified and pasteurizing egg products.
Increasingly, outbreaks of S. Enteritidis infection are associated with other foods, including meat, chicken, vegetables, dairy, and baked goods.
Salmonella serotype 4,[5],12:i:–, an antigenic variant of S. Typhimurium that lacks the second-stage flagellar antigen, has emerged since the 1990s as a foodborne pathogen primarily associated with pigs and pork products.
This serotype is the second most common NTS in Europe and the fifth most common in the United States.
These strains are MDR, with resistance to ampicillin, streptomycin, sulfonamides, and tetracycline.
Increasing reports of plasmid-mediated colistin resistance in these strains have been linked to international travel to Thailand and swine farm isolates.
Centralization of food processing and widespread food distribution have contributed to the increased incidence of NTS in developed countries.
NTS accounts for a significant majority of illnesses and hospitalizations associated with multistate foodborne outbreaks and retail food establishment outbreaks in the United States.
Manufactured foods to which recent multistate Salmonella outbreaks have been traced include peanut butter; milk products, including powdered infant formula; and various processed foods, including packaged breakfast cereal, salsa, frozen prepared meals, and snack foods.
Large outbreaks have also been linked to fresh produce, including alfalfa sprouts, nuts/seeds, cantaloupe, mangoes, papayas, tomatoes, and the herbal substance kratom consumed for its stimulant effect.
These items become contaminated by manure or water at a single site and then are widely distributed.
In the United States, NTS infection associated with exotic pets is an ongoing clinical and public health problem, especially from contact with reptiles or amphibians, including iguanas, snakes, turtles, and lizards.
Other pets, including hedgehogs, rodents, birds, baby chicks, ducklings, dogs, and cats, also are potential sources of NTS.
Compared with 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 United States, clinically important resistant NTS infections, defined as resistance to ampicillin or ceftriaxone or nonsusceptibility to ciprofloxacin, increased an estimated 40% during 2015–2016 (annual incidence ~220,000) compared with 2004–2008 (~159,000 infections).
The incidence (51.0 per 100,000 persons per year) and proportion of invasive NTS infections that are multidrug-resistant (75% with co-resistance to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol) is dramatically higher across all sub-Saharan African regions.
In the United States, infection with NTS with any antimicrobial resistance compared with NTS with no resistance are less likely to be associated with an outbreak and more likely to be associated with international travel, an increased risk of hospitalization, hospital length of stay, and death.

8. PROGNOSIS & COMPLICATIONS¶

Enteric fever is associated with an overall case-fatality rate of 2.5%, but mortality rates rise to 4.5% among hospitalized patients and to 10–30% if untreated.
Prompt administration of appropriate antibiotic therapy prevents severe complications of enteric fever and reduces mortality to 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.
In the United States, infection with NTS with any antimicrobial resistance compared with NTS with no resistance are less likely to be associated with an outbreak and more likely to be associated with international travel, an increased risk of hospitalization, hospital length of stay, and death.

9. SPECIAL CONSIDERATIONS¶

Unconjugated typhoid vaccines are poorly immunogenic in children <5 years of age because of limited ability to elicit T cell–dependent immune responses and immunologic memory.
Compared with unconjugated vaccines, typhoid Vi polysaccharide conjugated vaccines are effective in children <2 years of age and elicit substantially longer duration of protection.
The World Health Organization has recommended two typhoid conjugate vaccines (TCV) prioritized to prevent typhoid fever in countries with high incidence rates—Typbar TCV (manufactured by Bharat Biotech) in 2018 and TYPHIBEV (manufactured by Biological E) in 2020.
A single intramuscular 0.5-mL dose of either TCV is safe and 79–95% effective, with antibody response persisting up to 7 years.
As of 2023, TCV has been routinely introduced in national immunization programs in Pakistan, Nepal, Liberia, Zimbabwe, Malawi, Samoa.
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.
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.
Transmission via contaminated eggs can be prevented by cooking eggs until the yolk is solidified and pasteurizing egg products.
Increasingly, outbreaks of S. Enteritidis infection are associated with other foods, including meat, chicken, vegetables, dairy, and baked goods.
Salmonella serotype 4,[5],12:i:–, an antigenic variant of S. Typhimurium that lacks the second-stage flagellar antigen, has emerged since the 1990s as a foodborne pathogen primarily associated with pigs and pork products.
This serotype is the second most common NTS in Europe and the fifth most common in the United States.
These strains are MDR, with resistance to ampicillin, streptomycin, sulfonamides, and tetracycline.
Increasing reports of plasmid-mediated colistin resistance in these strains have been linked to international travel to Thailand and swine farm isolates.
Centralization of food processing and widespread food distribution have contributed to the increased incidence of NTS in developed countries.
NTS accounts for a significant majority of illnesses and hospitalizations associated with multistate foodborne outbreaks and retail food establishment outbreaks in the United States.
Manufactured foods to which recent multistate Salmonella outbreaks have been traced include peanut butter; milk products, including powdered infant formula; and various processed foods, including packaged breakfast cereal, salsa, frozen prepared meals, and snack foods.
Large outbreaks have also been linked to fresh produce, including alfalfa sprouts, nuts/seeds, cantaloupe, mangoes, papayas, tomatoes, and the herbal substance kratom consumed for its stimulant effect.
These items become contaminated by manure or water at a single site and then are widely distributed.
In the United States, NTS infection associated with exotic pets is an ongoing clinical and public health problem, especially from contact with reptiles or amphibians, including iguanas, snakes, turtles, and lizards.
Other pets, including hedgehogs, rodents, birds, baby chicks, ducklings, dogs, and cats, also are potential sources of NTS.
Compared with 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 United States, clinically important resistant NTS infections, defined as resistance to ampicillin or ceftriaxone or nonsusceptibility to ciprofloxacin, increased an estimated 40% during 2015–2016 (annual incidence ~220,000) compared with 2004–2008 (~159,000 infections).
The incidence (51.0 per 100,000 persons per year) and proportion of invasive NTS infections that are multidrug-resistant (75% with co-resistance to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol) is dramatically higher across all sub-Saharan African regions.
In the United States, infection with NTS with any antimicrobial resistance compared with NTS with no resistance are less likely to be associated with an outbreak and more likely to be associated with international travel, an increased risk of hospitalization, hospital length of stay, and death.

10. KEY PEARLS & CLINICAL TRAPS¶

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 most prominent symptom is prolonged fever (38.8°–40.5°C [101.8°–104.9°F]), which can continue for 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 (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.
In the United States, infection with NTS with any antimicrobial resistance compared with NTS with no resistance are less likely to be associated with an outbreak and more likely to be associated with international travel, an increased risk of hospitalization, hospital length of stay, and death.

Figures & Illustrations¶

Reproduced from Harrison's 22nd Edition.

Figure 1¶

Typical ileal perforation associated with Salmonella Typhi infection

Caption: FIGURE 171-3 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.) — FIGURE 171-1 Estimated national typhoid fever incidence and worldwide typhoid conjugate vaccine introduction, 2019–2022. Map showing incidence rates and vaccine rollout progress in endemic regions including India, Pakistan, and Africa.

Figure 2¶

Estimated national typhoid fever incidence and worldwide typhoid conjugate vaccine...

Caption: FIGURE 171-1 Estimated national typhoid fever incidence and worldwide typhoid conjugate vaccine introduction, 2019–2022. (Reproduced from M Hancuh et al: Typhoid fever surveillance incidence estimates, and progress toward typhoid conjugate vaccine introduction – Worldwide, 2018–2022. MMWR Morb Mortal Wkly Rep 72:171, 2023.) — FIGURE 171-2 'Rose spots,' the rash of enteric fever due to Salmonella Typhi or Salmonella Paratyphi. Faint, salmon-colored, blanching, maculopapular rash located primarily on the trunk and chest, evident in ~30% of patients.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.