Salmonellosis

AUTHOR: Glenn G. Fort, MD, MPH

Definition

Salmonellosis is an infection caused by one of several serotypes of a gram-negative bacillus of the genus Salmonella. Salmonella infection can be typhoidal (serotype Typhi or Paratyphi) or nontyphoidal. Current Salmonella nomenclature is described in Box 1.

BOX 1 Nomenclature of Salmonella Infections

The multiple microbiologic, serologic, and clinical designations applied to Salmonella infections are confusing.¹ Most pathogenic Salmonella belong to a single subspecies designated Salmonella enterica subspecies enterica. In addition to this species designation, Salmonella are classified serologically. The serogroup is assigned based on the O antigen alone, whereas the serotype designation, from which the name is derived, is based on both the O and H antigens.

Salmonella enterica subsp. enterica includes over 1400 serotypes. Although the full name of the cause of typhoid fever is Salmonella enterica subsp. enterica serotype Typhi, it is normally shortened to S. Typhi. Although serogroup designation is performed routinely in many laboratories, the test lacks clinical utility. Complete serotype identification is often performed in a reference laboratory; however, S. Typhi and Paratyphi A can also be identified by biochemical tests in a routine microbiology laboratory. Identification of S. Typhi and Paratyphi A are reviewed in detail in the World Health Organization’s “The Diagnosis, Treatment and Prevention of Typhoid Fever.” ²

Clinically Salmonella are classified as typhoidal or nontyphoidal. The typhoidal serotypes are S. Typhi and Paratyphi A, B, and C. All others are classified as nontyphoidal. However, this is also misleading, as many nontyphoidal strains also cause invasive infection, which may mimic typhoid fever.

Examples of Clinical and Serologic Classification of Pathogenic Salmonella
Clinical Classification	Serotype	Formal Designation	Serogroup
Typhoidal	Typhi	S. enterica subsp. enterica ser. Typhi	D
	Paratyphi A	S. enterica subsp. enterica ser. Paratyphi A	A
	Paratyphi B (schottmuelleri)	S. enterica subsp. enterica ser. Paratyphi B	B
	Paratyphi C (hirschfeldii)	S. enterica subsp. enterica ser. Paratyphi C	C
Nontyphoidal	Typhimurium	S. enterica subsp. enterica ser. Typhimurium	B
	Enteritidis	S. enterica subsp. enterica ser. Enteritidis	D
	Newport	S. enterica subsp. enterica ser. Newport	C

From Ryan ET et al: Hunter’s tropical medicine and emerging infectious diseases, ed 10, Philadelphia, 2019, Elsevier.

Synonyms

Typhoid fever

Paratyphoid fever

Enteric fever

ICD-10CM CODES
A02.0		Salmonella enteritis
A02.1		Salmonella sepsis
A02.2		Localized Salmonella infections
A02.8		Other specified Salmonella infections
A0.9		Salmonella infection, unspecified

Epidemiology & Demographics

Incidence (In U.S.)

Epidemiologically, the clinical syndromes are divided into those that cause a typhoidal type of infection (systemic illness with fever and abdominal pain) such as Salmonella typhi and those that do not: Nontyphoidal Salmonella infections (gastroenteritis) such as S. enteritidis, S. newport, and S. typhimurium.
Estimated 1 million cases/yr of nontyphoidal salmonellosis in the United States (leading cause of foodborne illness in the U.S.). In 2017 an outbreak occurred linked to live poultry in backyard flocks with over 960 cases in 48 states caused by several different Salmonella bacteria. In 2020 an outbreak associated with onions occurred in the U.S.
Largest outbreak of gastroenteritis syndrome (nontyphoidal): 200,000 who ingested contaminated milk.
Approximately 500 cases of Salmonella typhi infection are reported each year, of which nearly 80% is associated with foreign travel.

Predominant Age

<20 yr old.
>70 yr old.
Highest rates of infection in infants, especially neonates.

Peak Incidence

Summer and fall.

Genetics

Neonatal infection.

Highly susceptible to infection with nontyphoidal Salmonella.

TABLE 1 Clinical Features of Typhoid and Paratyphoid Fever

	Clinical Feature	Approx. Frequency ∗
	Fever	>95%
Flulike symptoms	Headache	80%
	Chills	40%
	Cough	30%
	Myalgia	20%
	Arthralgia	<5%
Abdominal symptoms	Anorexia	50%
	Abdominal pain	30%
	Diarrhea	20%
	Constipation	20%
Physical findings	Coated tongue	50%
	Hepatomegaly	10%
	Splenomegaly	10%
	Abdominal tenderness	5%
	Rash	<5%
	Generalized adenopathy	<5%

^∗The proportion of patients demonstrating these clinical features of enteric fever varies depending on the time, region, and type of clinical population (hospitalized or ambulatory) assessed. Estimates are drawn from case series in an endemic area presenting for ambulatory or inpatient care.

From Ryan ET et al: Hunter’s tropical medicine and emerging infectious diseases, ed 10, Philadelphia, 2019, Elsevier.

1 Brenner FW et al: Salmonella nomenclature, J Clin Microbiol 38:2465-2467, 2000.

2 World Health Organization: Background document: the diagnosis, treatment and prevention of typhoid fever, Geneva, 2003, WHO.

PHYSICAL FINDINGS & CLINICAL PRESENTATION (TABLE 1)

Infections:
1. Localized to GI tract (gastroenteritis)
2. Systemic (typhoid fever)
3. Localized outside of GI tract
Gastroenteritis:
1. Incubation period: 12 to 48 h
2. Nausea, vomiting
3. Diarrhea, abdominal cramps
4. Fever
5. Bacteremia: Occurs mostly in the immunocompromised host or those with underlying conditions, including HIV infection
6. Self-limited illness lasting 3 or 4 days
7. Colonization of GI tract persistent for months, especially in those treated with antibiotics
Typhoid fever:
1. Incubation period of few days to several wk
2. Prolonged fever, often with a stepwise-increasing temperature pattern
3. Myalgias
4. Headache, cough, sore throat
5. Malaise, anorexia
6. Abdominal pain
7. Hepatosplenomegaly
8. Diarrhea or constipation early in the course of illness
9. Rose spots (faint, maculopapular, blanching lesions) sometimes seen on chest or abdomen
Untreated disease:
1. Fever lasting 1 to 2 mo
2. Main complication: GI bleeding caused by perforation from ulceration of Peyer patches in the ileum
3. Rare complications:
  1. Mental status changes
  2. Shock
4. Relapse rate of approximately 10%
Infections outside GI tract:
1. Can occur in virtually any location
2. Usually occur in patients with underlying diseases
3. Endocarditis, endovascular infections are caused by seeding of atherosclerotic plaques or aneurysms
4. Hepatic or splenic abscesses in patients with underlying disease in these organs
5. Urinary tract infections in patients with renal tuberculosis (TB) or schistosomiasis
6. Salmonellae are a frequent cause of gram-negative meningitis in neonates
7. Osteomyelitis in children with hemoglobinopathies (particularly sickle cell disease)
8. Complications of typhoid and paratyphoid fever are summarized in Table 2

TABLE 2 Complications of Typhoid and Paratyphoid Fever

System	Complication	Notes
Gastrointestinal	Hemorrhage	10%-15% hospitalized patients
Gastrointestinal	Perforation	3% hospitalized patients
Hepatobiliary	Jaundice	1%-3% hospitalized patients
	Hepatitis	Usually subclinical (↑ ALT/AST)
	Acute cholecystitis	Rare, gallbladder may perforate
Neurologic	Mild encephalopathy	Confusion or apathy common
	Severe encephalopathy	Delirium, stupor, or coma
	Seizures	Common in children ≤5 yr
	Meningitis	Rare, primarily infants
	Guillain-Barré syndrome	Reported
Respiratory	Bronchitis	Cough is common
	Pneumonia	May be other concomitant bacterial infection (e.g., S. pneumoniae)
Cardiovascular	Myocarditis	Usually subclinical (ECG changes)
	Shock	Uncommon
Hematologic	Anemia	Usually subclinical
	DIC	Usually subclinical (↑ PT/PTT)
Other	Pyogenic infections	Uncommon
	Hemolytic uremic syndrome	Reported
	Miscarriage	Reported

ALT, Alanine aminotransferase; AST, aspartate aminotransferase; DIC, disseminated intravascular coagulation; ECG, echocardiogram; PT, prothrombin time; PTT, partial thromboplastin time.

From Ryan ET et al: Hunter’s tropical medicine and emerging infectious diseases, ed 10, Philadelphia, 2019, Elsevier.

ETIOLOGY

More than 2000 serotypes of Salmonella exist, but only a few cause disease in humans. Host factors and conditions predisposing to the development of systemic disease with nontyphoidal Salmonella strains are described in Table 3 and Table 4.
Raw produce is an increasingly recognized vehicle for salmonellosis. In 2008 there was a large outbreak due to contaminated jalapeno and Serrano peppers with Salmonella Saintpaul involving 1500 persons, of whom 21% were hospitalized and two died. In 2009 there was an outbreak associated with contaminated peanut butter and peanuts. In 2017 there was an outbreak associated with papaya.
Some found only in humans are the cause of enteric fever:
1. S. typhi
2. S. paratyphi
Some responsible for gastroenteritis and frequently isolated from raw meat and poultry and uncooked or undercooked eggs:
1. S. typhimurium
2. S. enteritidis
S. choleraesuis is a prototype organism that causes extraintestinal nontyphoidal disease.
Transmission generally via ingestion of contaminated food or drink.
Outbreaks of gastroenteritis related to contaminated poultry, meat, and dairy products are common.
Typhoid fever is a systemic illness caused by serotypes exclusive to humans:
1. Acquisition by ingestion of food or water contaminated by other humans.
2. Most cases in the United States are:
  1. Acquired during foreign travel: 80% of cases.
  2. Acquired by ingestion of food prepared by chronic carriers, many of whom have acquired the organism outside of the United States.

TABLE 3 Host Factors and Conditions Predisposing to the Development of Systemic Disease With Nontyphoidal Salmonella Strains

Neonates and young infants (≤3 mo of age)
HIV/AIDS
Other immunodeficiencies and chronic granulomatous disease
Immunosuppressive and corticosteroid therapies
Malignancies, especially leukemia and lymphoma
Hemolytic anemia, including sickle cell disease, malaria, and bartonellosis
Collagen vascular disease
Inflammatory bowel disease
Achlorhydria or use of antacid medications
Impaired intestinal motility
Schistosomiasis, malaria
Malnutrition

AIDS, Acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.

From Kliegman RM et al: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011, Saunders.

TABLE 4 Susceptibility to Salmonella spp. Infection

Patient Group at Risk		Mechanism
Newborn		Achlorhydria, rapid gastric emptying
		Poorly developed cell-mediated immunity
		Complement deficiency
		Immunoglobulin deficiency in premature infants
Sickle-cell anemia		Reticuloendothelial system overload owing to hemolysis
		Functional asplenia
		Tissue infarcts
		Defective opsonization
Neutropenia (congenital or acquired)		Polymorphonuclear neutrophils needed for killing
Chronic granulomatous disease		Defective killing by polymorphonuclear neutrophils
Defects of immune system interleukin (IL)-12/interferon-γ axis		Defective signaling resulting in failure to activate macrophages and recurrent/persistent infection by nontyphoid Salmonella
Acquired immunodeficiency syndrome		Low CD4
		Effects of malnutrition on cell-mediated immunity
		Survival of organisms in macrophages (owing to Salmonella genes PhoP/PhoQ, spvA-D, R )
Organ transplantation, immunosuppression		Defective cell-mediated immunity
Gastrectomy		Loss of stomach acid barrier
Malaria		Reticuloendothelial overload during hemolysis
		Abnormal complement levels
		Abnormal macrophage function
Bartonellosis (verruga peruana)		Reticuloendothelial overload during hemolysis
Schistosomiasis		Salmonella sequestered in schistosomes protected from host defenses and antibiotics

From Cherry JD et al: Feigin and Cherry’s textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

Differential Diagnosis

Other causes of prolonged fever:
1. Malaria
2. TB
3. Brucellosis
4. Amebic liver abscess
Other causes of gastroenteritis:
1. Bacterial: Shigella, Yersinia, Campylobacter spp.
2. Viral: Norwalk virus, rotavirus
3. Parasitic: Entamoeba histolytica, Giardia lamblia
4. Toxic: Enterotoxigenic E. coli, Clostridium difficile

Workup

Typhoid fever:
1. Cultures of blood, stool, urine; repeat if initially negative.
2. Blood cultures are more likely to be positive early in the course of illness.
3. Stool and urine cultures are more commonly positive in the second and third wk of illness.
4. Highest yield with bone marrow biopsy cultures: 90% positive.
5. Serology using Widal test is helpful in retrospect, showing a fourfold increase in convalescent titers.
Gastroenteritis: Stool cultures and/or newer polymerase chain reaction (PCR) gastrointestinal panels
Extraintestinal localized infection:
1. Blood cultures.
2. Cultures from the site of infection.

Laboratory Tests

Neutropenia is common.
Transaminitis is possible.
Culture to grow organism: Blood, body fluids, biopsy specimens.

Imaging Studies

Not routinely indicated.
Radiographs of bone may be suggestive of osteomyelitis (particularly in patients with sickle cell disease and bone infarctions).
Computed tomography (CT) scan or sonogram of abdomen:
1. May reveal hepatic or splenic abscesses or pleural involvement
2. May reveal aortic aneurysm

Nonpharmacologic Therapy

Adequate hydration and electrolyte replacement in people with diarrhea.

Acute General Rx

Treatment decisions must consider the severity of infection and the risk for extraintestinal disease.

Typhoid fever:
1. Levofloxacin 750 mg orally (PO)/intravenous (IV) q24h or ciprofloxacin 500 mg PO bid or 400 mg IV bid for 7 to 10 days. Should not be used as first line in patients from South Asia due to resistance unless known to be susceptible
2. Ceftriaxone 2 g IV qd for 7 to 14 days or cefixime (20-30 mg/kg/day orally divided into q12h dosing for 7 to 14 days)
3. Another alternative agent: Azithromycin (1 g orally then 500 mg daily for 5 to 7 days)
4. Children (Table 5): In general, quinolones are avoided in children unless a multidrug-resistant strain is involved due to concerns of possible cartilage damage. Another alternative for children: Azithromycin (10-20 mg/kg to 1 g maximum once daily for 5-7 days)
5. If tests show susceptibility, can also use amoxicillin or trimethoprim/sulfamethoxazole in adults and children (Table 6)
6. Dexamethasone 3 mg IV initially, followed by 1 mg IV q6h for eight doses for patients with shock or mental status changes
Gastroenteritis:
1. Usually not indicated for gastroenteritis alone because this illness usually self-limited
2. Treatment may prolong the carrier state and is discouraged for healthy patients <50 yr of age who have relatively mild disease
3. Prophylactic treatment for patients who are at high risk of developing complications from bacteremia (see Table 5):
  1. Neonates
  2. Patients with hemoglobinopathies
  3. Patients with atherosclerosis
  4. Patients with aneurysms
  5. Patients with prosthetic devices
  6. Immunocompromised patients

TABLE 6 Antibiotics Commonly Used in the Treatment of Salmonella Infections

Drug	Dose	Comments
Ciprofloxacin	20-30 mg/kg per day in 2 doses PO or IV	First-line therapy ^a
Ceftriaxone	75-100 mg/kg per day in 1 or 2 doses IM or IV	First-line therapy
Cefotaxime	100-300 mg/kg per day in 3-4 doses IM or IV	First-line therapy
Cefixime	20-30 mg/kg per day in 1 or 2 doses PO	Alternative therapy
Azithromycin	10 mg/kg per day in 1 dose PO	Alternative therapy
Chloramphenicol	50-100 mg/kg per day in 4 doses PO	High frequency of resistance; use only for susceptible strains
Ampicillin	200-400 mg/kg per day in 4 doses PO, IM, or IV	High frequency of resistance; use only for susceptible strains
TMP-SMX	10 mg/kg per day TMP, 50 mg/kg per day SMX in 2 doses PO or IV	High frequency of resistance; use only for susceptible strains

IM, Intramuscular; IV, intravenous; PO, by mouth; TMP-SMX, trimethoprim-sulfamethoxazole.

^aNot approved by the US Food and Drug Administration in children <18 yr; current expert opinion agrees in recommending this agent as an effective therapy for regions with susceptible Salmonella strains and especially for severe infections.

From Cherry JD et al: Feigin and Cherry’s textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

TABLE 5 Treatment of Salmonella Gastroenteritis in Children

Organism and Indication		Dose and Duration of Treatment
Salmonella infections in infants <3 mo of age or immunocompromised persons (in addition to appropriate treatment for underlying disorder)		Cefotaxime 100-200 mg/kg/day every 6 hr for 5-14 days or Ceftriaxone 75 mg/kg/day once daily for 7 days or Ampicillin 100 mg/kg/day every 6 hr for 7 days or Cefixime 15 mg/kg/day for 7-10 days

From Kliegman RM et al: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011, Saunders.

Chronic Rx

Carrier states are possible in those with typhoid fever.
More common in people >60 yr of age and in people with gallstones.
Usual site of colonization is the gallbladder.
Treatment should be considered for those with persistently positive stool cultures and for food handlers.
Suggested regimens for eradication of carrier state:
1. Ciprofloxacin 500 mg PO bid for 4 wk.
2. SMX/TMP 1 to 2 DS tabs PO bid for 6 wk (if susceptible).
3. Amoxicillin 2 g PO q8h for 6 wk (if susceptible).
Cholecystectomy may be required in carriers with gallstones who fail medical therapy, but this is rarely indicated for nontyphoidal salmonellosis currently.
Prolonged course of oral therapy or lifetime suppression for patients with AIDS who have chronic infection.

Disposition

Typhoid fever:
1. Treated patients usually respond to therapy; small percentage of chronic carriers.
2. Untreated patients may have serious complications.
Gastroenteritis:
1. Usually self-limited
2. May be recurrent or persistent in AIDS patients

Comments

Fluoroquinolones remain the most reliably effective class of antibiotics for empiric therapy despite increasing resistance. They should not be used in children or pregnant women.
Infections should be reported to local health departments.
Other recent outbreaks in the U.S. have been traced back to raw tomatoes, peanut butter, pet turtles, frozen pot pies, and onions. In 2022 outbreaks occurred related to backyard poultry and pet turtles less than 4 inches in size.
Vaccine is available for Salmonella typhi: Oral live weakened vaccine (four doses, one every other day) for age >6 yr and lasts for 5 yr or one dose of inactivated injectable vaccine for persons >2 yr old that lasts for 2 yr, but neither vaccine is greater than 75% effective.
Outbreaks of extensively drug resistant (XDR) typhoid fever have occurred in Pakistan (resistant to ampicillin, sulfa, chloramphenicol, quinolones, and ceftriaxone). Drug of choice for these cases has been azithromycin for milder cases and carbapenems for more severe cases. Some of these cases have been detected in travelers returning from Pakistan.

Related Content

Salmonellosis (Patient Information)

Typhoid Fever (Related Key Topic)

Bula-Rudas F.J. : Salmonella infections in childhoodAdv Pediatr. ;62:29-58, 2015.
DuPont H.L. : Acute infectious diarrhea in immunocompetent adultsN Engl J Med. ;370:1532-1540, 2014.
Gut A.M. : Salmonella infection-prevention and treatment by antibiotics and probiotic yeasts: a reviewMicrobiology. ;164:1327-1344, 2018.
Haselbeck A.H. : Current perspectives on invasive nontyphoidal Salmonella diseaseCurr Opin Infect Dis. ;30:498-503, 2017.

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