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Salmonellosis¶

Part 5: Infectious Diseases | Part 5 – Infectious Diseases: Bacterial · Part 5 – Infectious Diseases: Bacterial · Chapter 171

Key Clinical Points¶

Enteric (typhoid) fever caused by S. Typhi/Paratyphi; NTS infects humans and animals.
Rose spots (30% of typhoid cases): salmon-colored, blanching maculopapular rash on trunk/chest.
Relative bradycardia (Faget sign) occurs in ~50% of enteric fever patients.
Intestinal perforation/bleeding occurs in weeks 3-4 due to Peyer's patch hyperplasia/ulceration.
Chronic carriage (>1 year) occurs in 2-5% of untreated patients, more common in women/biliary abnormalities.
MDR S. Typhi (DSC) and XDR H58 clone prevalent in Indian subcontinent/Pakistan; empiric carbapenems/azithromycin required.
Typhoid conjugate vaccines (TCV) effective in children <2 years; Vi/Ty21a less effective.
NTS is second most common foodborne pathogen in US (after Campylobacter); S. Enteritidis/Typhimurium most common serotypes.
Invasive NTS (ST313) emerging in sub-Saharan Africa with nonspecific febrile illness similar to enteric fever.
Bone marrow culture (~80% sensitivity) preferred over blood culture (~40-60% sensitivity) for typhoid diagnosis.

DEFINITION & CLASSIFICATION¶

• Definition (Harrison's 22e): Bacteria of the genus Salmonella are highly adapted for growth in both humans and animals and cause a wide spectrum of disease.

• Clinical Distinction: ◦ S. Typhi/Paratyphi: Restricted to human hosts; causes enteric fever. ◦ Nontyphoidal Salmonella (NTS): Infects humans and animals; causes gastroenteritis and bacteremia.

• Classification Details: ◦ >200 serotypes pathogenic to humans. ◦ Classified by O antigen, Vi antigen (S. Typhi/Paratyphi C), and H antigen. ◦ All except S. Gallinarum-Pullorum are motile via peritrichous flagella. ◦ Only 1% of clinical isolates ferment lactose.

1.1 Taxonomy & Classification¶

• Taxonomy: ◦ Includes S. enterica (6 subspecies) and S. bongori. ◦ S. enterica subspecies I contains most human-pathogenic serotypes. ◦ >2600 serovars classified by antigenic variation of O, Vi, and H antigens.

• Identification: ◦ Serotyping identifies 99% of human infections via agglutination reactions (serogroups A-E). ◦ Common names used: S. Typhimurium instead of full taxonomic designation.

EPIDEMIOLOGY¶

• Enteric Fever: ◦ No animal reservoir; transmitted via fecal-oral route.

• NTS: ◦ >200 serotypes; S. Typhimurium and S. Enteritidis are most common globally.

• Global Burden: ◦ 93–150 million NTS infections/year → 60,000–155,000 deaths. ◦ 9.2–21 million typhoid cases/year. ◦ High incidence in Indian subcontinent (1000+ cases/100,000 children in urban areas).

• Risk Factors: ◦ Contaminated water/food, poor sanitation, travel to endemic regions, immunocompromise.

2.1 Global Burden and Transmission¶

• US Statistics: ◦ 5700 cases/year; 78% linked to international travel (India/Pakistan/Bangladesh). ◦ NTS incidence in US: 14.5/100,000 (2nd highest after Campylobacter).

• Invasive NTS (ST313): ◦ ~535,000 cases/year globally; 80% in sub-Saharan Africa.

• Transmission Routes: ◦ Foodborne (eggs/poultry), zoonotic (reptiles/amphibians), person-to-person (invasive strains).

2.2 Antimicrobial Resistance Trends¶

• S. Typhi Trends: ◦ MDR emerged in 1980s; DSC (ciprofloxacin resistance) on Indian subcontinent. ◦ XDR H58 clone (ESBL resistance) dominant in Pakistan, spreading via air travel. ◦ Azithromycin resistance linked to mass treatment for trachoma and typhoid.

• NTS Trends: ◦ 75% of S. Typhimurium ST313 are MDR; some resistant to ceftriaxone/azithromycin.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Infection Initiation: ◦ Ingestion of 200–10^6 CFU via contaminated food/water. ◦ Risk factors: low stomach acidity (infants, PPI use), intestinal barrier disruption (IBD, antibiotics).

• Mechanism of Invasion: ◦ S. Typhi/Paratyphi invade small intestine via M cells in Peyer's patches using type III secretion systems. ◦ Survive macrophage activity via PhoP/PhoQ regulatory system and second type III secretion system.

3.1 Enteric (Typhoid) Fever Pathogenesis¶

• Systemic Spread: ◦ Dissemination via lymphatics to reticuloendothelial tissues (liver/spleen/bone marrow).

• Clinical Progression: ◦ Initial asymptomatic phase → fever/abdominal pain from macrophage cytokine release. ◦ Hepatosplenomegaly develops with acquired immune response. ◦ Peyer's patch necrosis in weeks 3–4.

• Chronic Carriage: ◦ 2–5% of untreated patients; more common in women/biliary disease.

3.2 NTS Gastroenteritis Pathogenesis¶

• Inflammatory Response: ◦ Massive PMN infiltration into bowel mucosa via IL-8 induction and inflammasome activation. ◦ Neutrophil degranulation → intestinal mucosal damage and inflammatory diarrhea.

• Persistence: ◦ Tetrathionate utilization in inflamed gut allows NTS persistence despite competition with flora.

• Typhoidal vs. NTS: ◦ Typhoidal strains lack butyrate metabolism and intestinal colonization capacity, favoring systemic spread.

CLINICAL FEATURES¶

• Enteric Fever Symptoms: ◦ Prolonged fever (38.8–40.5°C), abdominal pain (30–40%), headache (80%), coated tongue (51–56%).

• Key Physical Findings: ◦ Rose spots (30%): salmon-colored, blanching maculopapular rash on trunk/chest (Figure 171-2). ◦ Relative bradycardia (Faget sign) in ~50% of cases despite high fever. ◦ Splenomegaly (5–6%), hepatomegaly (3–6%), epistaxis.

• NTS Gastroenteritis Symptoms: ◦ Acute diarrhea (22–28%), vomiting (18%), abdominal pain (30–40%). ◦ Fever less common than in enteric fever.

• Invasive NTS (ST313): ◦ Nonspecific febrile illness without diarrhea, mimicking typhoid.

4.1 Enteric Fever Clinical Presentation¶

• Duration: Prolonged fever (up to 4 weeks if untreated). ◦ S. Paratyphi A: milder disease with more gastrointestinal symptoms than S. Typhi.

4.2 NTS Gastroenteritis Clinical Presentation¶

• Risk Groups: Higher mortality in elderly/immunocompromised (HIV, hemoglobinopathies).

DIFFERENTIAL DIAGNOSIS¶

• Enteric Fever Differentials: ◦ Typhus, malaria, leptospirosis, brucellosis, HIV enteropathy.

• NTS Gastroenteritis Differentials: ◦ Campylobacter, E. coli O157:H7, Shigella, norovirus, giardiasis.

DIAGNOSTIC APPROACH¶

Blood Culture: ◦ Sensitivity: 40–60% for typhoid. ◦ Note: Reduced by prior antibiotics.
Bone Marrow Culture: ◦ Sensitivity: ~80%. ◦ Status: Preferred diagnostic method/gold standard.
Stool Culture: ◦ Use: Useful for NTS; not useful for S. Typhi/Paratyphi.
Molecular Tests (PCR): ◦ Use: Detects S. Typhi/Paratyphi DNA in blood/stool with high specificity.
Serology (Widal Test): ◦ Sensitivity: 30–50%. ◦ Specificity: 60–70%. ◦ Note: Not recommended for diagnosis due to cross-reactivity.

6.1 Diagnostic Test Summary¶

• Comparison of Methods: ◦ Bone marrow culture (80%) > blood culture (40–60%). ◦ PCR (75–90% sensitivity, 99% specificity) is highly specific.

MANAGEMENT & TREATMENT¶

Enteric Fever Treatment: • Empirical/Susceptible: Ceftriaxone (2 g/d IV), Azithromycin (1 g/d PO), or Fluoroquinolones (if not DSC). • MDR/XDR Cases: Meropenem (1 g q8h IV) or Azithromycin (1 g/d PO). • Duration: 7–14 days for acute; 28 days for carriage.
NTS Treatment: • Preemptive: Ciprofloxacin (500 mg bid PO). • Severe Gastroenteritis: Ceftriaxone, Ciprofloxacin, Azithromycin, TMP-SMX, or Amoxicillin. • Bacteremia: Ceftriaxone (2 g/d IV) or Ciprofloxacin (400 mg q12h IV → 500 mg bid PO). • Endocarditis/Arteritis: Ceftriaxone, Ciprofloxacin, or Ampicillin. • Meningitis: Ceftriaxone (2 g q12h IV) or Ampicillin (2 g q4h IV).
Prevention & Control: • Typhoid Conjugate Vaccine (TCV): 85% efficacy in children <2 years; recommended for endemic regions. • Vi Polysaccharide Vaccine: 50–60% efficacy; not effective in children <2 years. • Food Safety: Avoid raw eggs, undercooked poultry, untreated water.

7.1 Antibiotic Regimens for Enteric Fever¶

7.2 NTS Treatment Summary¶

• Preemptive: Ciprofloxacin (500 mg bid PO). • Bacteremia: Ceftriaxone (2 g/d IV) or Cipro (400 mg q12h IV → 500 mg bid PO). • Meningitis: Ceftriaxone (2 g q12h IV) or Ampicillin (2 g q4h IV).

COMPLICATIONS & PROGNOSIS¶

• Enteric Fever Prognosis: ◦ Mortality: ~1–2% with treatment; 10–30% without.

• Complications: ◦ Intestinal perforation (1–2%) (Figure 171-3). ◦ GI bleeding, sepsis, myocarditis, encephalopathy.

• NTS Prognosis: ◦ Mortality <1% in immunocompetent; higher in elderly/immunocompromised.

• Chronic Carriage: ◦ 2–5% of untreated patients; increased gallbladder cancer risk (Indian subcontinent).

SPECIAL POPULATIONS¶

• Invasive NTS (ST313): ◦ Requires empirical broad-spectrum antibiotics (ceftriaxone, azithromycin).

• Exotic Pet Exposure: ◦ Reptiles/amphibians are major zoonotic sources; children <5 years at highest risk.

• Multidrug Resistance: ◦ Linked to agricultural antibiotic use and international travel.

KEY PEARLS & HIGH-YIELD POINTS¶

• Rose spots are pathognomonic for typhoid but only present in ~30% of cases. • Relative bradycardia is absent in 50% of enteric fever patients; not a reliable sign. • Bone marrow culture is the gold standard for typhoid diagnosis (80% sensitivity). • NTS gastroenteritis often presents without diarrhea; may mimic viral gastroenteritis. • XDR S. Typhi H58 clone now dominant in Pakistan; requires carbapenems/azithromycin.

Reference Tables¶

TABLE 171-1 Antibiotic Therapy for Enteric Fever in Adults INDICATION Empirical Treatment¶

Harrison's 22e, p.1318

INDICATION	AGENT	DOSAGE (ROUTE)	DURATION, DAYS
Empirical Treatment
	Ceftriaxonea	2 g/d (IV)	10–14
	Ciprofloxacinb	500 mg bid (PO) or 400 mg q12h (IV)	5–7
	Azithromycinc	1 g/d (PO)	5
Fully Susceptible
	Ceftriaxone Ciprofloxacin Azithromycin	2 g/d (IV) 500 mg bid (PO) or 400 mg q12h (IV) 1 g/d (PO)
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 Ciprofloxacin Azithromycin	2 g/d (IV) 500 mg bid (PO) or 400 mg q12h (IV) 1 g/d (PO)
Ceftriaxone-Resistant
Optimal treatment	Meropenemd Azithromycin	1 g q8h (IV) 1 g/d (PO)	10–14 5
Eradication of Carriage
	Ciprofloxacin	500–750 mg bid (PO)
Alternative treatment	Azithromycin	500 mg (PO)	28

TABLE 171-2 Antibiotic Therapy for Nontyphoidal Salmonella Infection in Adults INDICATION Preemptive Treatment a Severe…¶

Harrison's 22e, p.1321

INDICATION	AGENT	DOSAGE (ROUTE)	DURATION, DAYS
Preemptive Treatmenta
	Ciprofloxacinb	500 mg bid (PO)	2–3
Severe Gastroenteritisc
Ciprofloxacin Azithromycin Trimethoprim- sulfamethoxazole Amoxicillin Ceftriaxone	500 mg bid (PO) or 400 mg q12h (IV) 500 mg once daily 160/800 mg bid (PO) 1 g tid (PO) 1–2 g/d (IV)
Bacteremia
	Ceftriaxoned	2 g/d (IV)	7–14
	Ciprofloxacin	400 mg q12h (IV), then 500 mg bid (PO)
Endocarditis or Arteritis
Ceftriaxone Ciprofloxacin Ampicillin	2 g/d (IV) 400 mg q8h (IV), then 750 mg bid (PO) 2 g q4h (IV)
Meningitis
	Ceftriaxone	2 g q12h (IV)	14–21
	Ampicillin	2 g q4h (IV)
Other Localized Infection
Ceftriaxone Ciprofloxacin Ampicillin	2 g/d (IV) 500 mg bid (PO) or 400 mg q12h (IV) 2 g q6h (IV)