Download PDF

Plague and Other Yersinia Infections¶

Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial · Part 5 – Infectious Diseases: Bacterial · Chapter 176

Key Clinical Points¶

Plague is a systemic zoonosis caused by Y. pestis, primarily transmitted via flea bites or respiratory droplets.
Bubonic plague presents with sudden fever and tender, boggy buboes; pneumonic plague has rapid progression and high mortality if untreated.
Y. pestis exhibits bipolar staining (closed safety pin appearance) on Wayson/Giemsa stain and lacks motility at 37°C.
First-line treatment includes Gentamicin (5 mg/kg q24h), Streptomycin (2 g q12h), or Levofloxacin; mortality drops from 98% to 17% with timely treatment.
WHO case definitions require epidemiological context plus F1 antigen, culture, or PCR for confirmation.
Tularemia (Francisella tularensis) is a bioterrorism risk agent; experimental treatments include gepotidacin and passive immunization.
Y. pestis grows optimally at 25–29°C, forming pinpoint colonies on sheep blood agar within 24 hours.

1. DEFINITION & OVERVIEW¶

• Plague: Systemic zoonosis caused by Yersinia pestis. ◦ Primarily affects small rodents in rural areas of Africa, Asia, and the Americas. ◦ Transmission: Flea bites or contact with infected tissues/respiratory droplets.

Definition (Harrison's 22e): Plague is a systemic zoonosis caused by Yersinia pestis. It predominantly affects small rodents in rural areas of Africa, Asia, and the Americas and is usually transmitted to humans by an arthropod vector (the flea).

• Tularemia: Distinct infection from Francisella tularensis.

Definition (Harrison's 22e): Tularemia is caused by Francisella tularensis, a variety of Yersinia-like bacteria.

2. EPIDEMIOLOGY¶

• Transmission Dynamics: Human plague follows rodent epizootics → fleas seek new hosts after mass rodent deaths. • Endemic Regions: Africa, Asia, and the Americas; U.S. cases cluster in Four Corners region and western states. • Global Statistics: 2886 global cases (17% fatality) reported to WHO (2013–2018); U.S. incidence fell to ≈7/year post-2000. • Human Transmission: Person-to-person transmission occurred in 2014 Colorado outbreak and historically in 1924 Los Angeles epidemic.

2.1 Tularemia Epidemiology¶

• Mortality: Type B F. tularensis has <1% fatality rate with early treatment (median initiation at 7 days post-onset). • Complications: Rates <10% due to prompt antimicrobial use. • Respiratory/Pneumonic Tularemia: 1.5% mortality reported in Sweden.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

• Evolution: Y. pestis evolved from Y. pseudotuberculosis via plasmid acquisitions (pla, ymt) and gene inactivation. • Flea Transmission: Biofilm formation in proventriculus → blockage → bacterial inoculation during feeding. • Mammalian Pathogenesis: Pla protease facilitates lymphatic spread; F1 capsule enhances flea-to-mammal transmission. • Immune Evasion: LcrV-mediated anti-inflammatory effects and modified LPS to suppress TLR4 activation.

3.1 Tularemia Pathogenesis¶

• Early Treatment Impact: Initiation at median 7 days post-onset reduces complications (<10% lymphadenopathy rate). • Fetal Risk: F. tularensis can cross placenta → fetal infection without maternal treatment.

4. CLINICAL FEATURES¶

• Bubonic Plague: ◦ Incubation: 2–6 days. ◦ Presentation: Sudden fever (>38°C), tender inguinal/cervical buboes with boggy consistency. • Septicemic Plague: ◦ Prevalence: 10–25% of cases present with shock without preceding lymphadenopathy. ◦ Risk Factor: Higher risk in patients >40 years old. • Pneumonic Plague: ◦ Incubation: 1–7 days. ◦ Presentation: Rapid onset of fever, cough, dyspnea, and hemoptysis; potential for bioterrorism spread. • Pharyngeal Plague: ◦ Cause: Consumption of infected meat. ◦ Presentation: Resembles tonsillitis with cervical lymphadenopathy.

4.1 Tularemia Clinical Features¶

• Complication Rates: <10% due to early antibiotic use (median 7 days post-onset).

5. DIFFERENTIAL DIAGNOSIS¶

• Bubonic Plague: Distinguish from streptococcal/staphylococcal lymphadenitis, cat-scratch disease, and filariasis (absent cellulitis/lymphangitis). • Pneumonic Plague: Differentiate from community-acquired pneumonia and bioterrorism aerosol release. • Septicemic Plague: Distinguish from other gram-negative sepsis and DIC. • Meningitis: Differentiate from bacterial meningitis and subarachnoid hemorrhage. • Pharyngitis: Distinguish from tonsillitis and infectious mononucleosis.

6. INVESTIGATIONS & DIAGNOSIS¶

Initial Assessment: Clinical presentation + epidemiological context (exposure to infected humans/animals or residence in/travel to a known endemic focus within 10 days).
Suspected Case: Clinical presentation suggestive of plague AND epidemiological context.
Probable Case: Suspected case PLUS one of the following: ◦ F1 antigen detected in bubo aspirate, sputum, blood, or postmortem tissues (rapid antigen test or direct immunofluorescence). ◦ Single anti-1 serology without evidence of previous infection/immunization. ◦ Direct microscopy: gram-negative coccobacilli with bipolar staining (Wayson or Wright-Giemsa).
Confirmed Case: Suspected case PLUS at least one of the following: ◦ Isolation of Y. pestis from clinical sample (requires 2 of 3: phage lysis at 20–25°C and 37°C; biochemical profile; F1 antigen detection). ◦ Seroconversion or ≥4-fold difference in anti-F1 antibody titer in paired serum samples drawn ≥2 weeks apart. ◦ Y. pestis DNA positive by species-specific PCR on clinical sample or culture.
Not a Case (Exclusion): ◦ Suspected case AND [two negative lab tests (antigen, microscopy, serology, culture, or PCR) OR two negative rapid antigen tests for F1 antigen on 2 clinical specimens collected at 24-h intervals when no other confirmatory tests are possible].
Laboratory Characteristics: ◦ Morphology: Bipolar staining (safety pin), rod-shaped. ◦ Growth: No motility at 37°C; pinpoint colonies on sheep blood agar within 24 hours.

6.1 Tularemia Investigations¶

• Experimental Options: Gepotidacin (inhibits DNA gyrase/topoisomerase IV, no fluoroquinolone cross-resistance) and passive immunization with F. tularensis-specific antibodies.

7. MANAGEMENT & TREATMENT¶

First-line Treatment (Plague): ◦ Gentamicin: 5 mg/kg q24h (IM/IV); Child: 4.5–7.5 mg/kg q24h. ◦ Streptomycin: 2 g q12h (IM/IV); Child: 30 mg/kg (max 1 g per dose) q12h. ◦ Levofloxacin: Adult (>50 kg): 750 (500–750) mg q24h; Child (<50 kg, ≥6 months): 16 mg/kg (max 250 mg) q12h.
Alternative Options: ◦ Ciprofloxacin: Adult: 1500 mg q12h; Child: 30–45 mg/kg (max 500 mg) q8–12h. ◦ Moxifloxacin: 400 mg q24h. ◦ Doxycycline: Adult: 200 mg (with 200 mg loading dose) q12h; Child: 4.4 mg/kg (max 100 mg, with 4.4 mg/kg loading dose) q12h. ◦ Tetracycline: Adult: 2 g q6h; Child (>8 y): 40–50 mg/kg q6h. ◦ Chloramphenicol: 50–100 mg/kg q6h.
Prophylaxis: ◦ Doxycycline: Adult: 200 mg q12h or q24h; Child (≥8 y): ≥45 kg (adult dose) or ≤45 kg (4.4 mg/kg max 200 mg) q12h. ◦ Levofloxacin: Adult and child >50 kg: 500–750 mg q24h; Child <50 kg and ≥6 months: 16 mg/kg (max 250 mg) q12h. ◦ Ciprofloxacin: 1–1.5 g q12h or 30 mg/kg (max 750 mg) q12h.
Tularemia Treatment: ◦ Experimental: Gepotidacin and passive immunization. ◦ Pregnancy: Antibiotic treatment required to prevent fetal complications.

Table 2 & 3 Summary¶

• Table 176-2 (Treatment): Includes Gentamicin, Streptomycin, Levofloxacin, Ciprofloxacin, Moxifloxacin, Doxycycline, Tetracycline, and Chloramphenicol. • Table 176-3 (Prophylaxis): Includes Doxycycline, Levofloxacin, and Ciprofloxacin.

8. PROGNOSIS & COMPLICATIONS¶

• Pneumonic Plague Mortality: 98% untreated → 17% with timely treatment. • Septicemic Progression: May progress to DIC (low platelets, prolonged PT, elevated fibrinogen degradation products). • Bubo Persistence: May persist >1 week post-treatment but resolve without sequelae. • Tularema Complications: Reduced to <10% with early antibiotic use.

9. SPECIAL CONSIDERATIONS¶

• Pregnancy (Tularemia): Antibiotic treatment is mandatory to prevent transplacental transmission and fetal complications. • Pediatrics: Tetracyclines are contraindicated in children <7 years; Doxycycline used for ≥8 years.

9.1 Tularemia Prevention¶

• No licensed vaccine for tularemia; focus on avoiding tick/flea exposure and using personal protective equipment.

10. KEY PEARLS & CLINICAL TRAPS¶

• Rapid Diagnosis: F1 antigen detection has high negative predictive value for pneumonic plague. • Morphology: 'Safety pin' appearance (bipolar staining) is a hallmark of Y. pestis. • Growth: Y. pestis grows at 25–29°C; lack of motility at 37°C distinguishes it from some other pathogens. • Tularemia Risk: High risk of fetal infection if untreated in pregnancy.

Reference Tables¶

TABLE 176-1 World Health Organization Case Definitions of Plague Suspected Case Clinical presentation suggestive of…¶

Harrison's 22e, p.1345

Suspected Case
Clinical presentation suggestive of plague
And
Epidemiological context suggesting possible exposure to plague (exposure to
infected humans or animals, or residence in or travel to a known endemic focus
within 10 days prior to onset of the disease)
Probable Case
Meeting the definition of a suspected case
plus 1 of the following
• F1 antigen detected in bubo aspirate, sputum, blood, or postmortem tissues by
rapid antigen test or direct immunofluorescence
• A single anti-F1 serology without evidence of previous Yersinia pestis infection
or immunization
• Direct microscopy in a clinical sample: gram-negative coccobacilli that
display bipolar staining with Wayson or Wright-Giemsa stain
Confirmed Case
Meeting the definition of a suspected case
Plus at least 1 of the following
• Isolation of Y. pestis from a clinical sample (based on appropriate colonial
morphology and at least 2 of the following tests positive: phage lysis of
cultures at 20–25°C and 37°C; biochemical profile; F1 antigen detection)
• Seroconversion or a fourfold difference in anti-F1 antibody titer in paired
serum samples drawn at least 2 weeks apart
• Y. pestis DNA positive by species-specific PCR on either clinical sample or
culture
Not a case (exclusion of diagnosis)
Meeting the definition of a suspected case
And either of the following
• At least two laboratory tests (rapid antigen test or direct immunofluorescence
against F1 antigen, direct microscopy, convalescent serology, culture, PCR)
are conducted AND they are negative
• When no confirmatory tests can be performed, 2 negative rapid antigen tests
for F1 antigen on 2 clinical specimens collected at 24-h intervals

TABLE 176-2 Guidelines for the Treatment of Plague DRUG Gentamicin Adult Child Streptomycin Adult Child Levofloxacin…¶

Harrison's 22e, p.1346

DRUG	DAILY DOSE	DOSING INTERVAL, h	ROUTE
Gentamicin
Adult	5 mg/kga	24	IM/IV
Child	4.5–7.5 mg/kga	24	IM/IV
Streptomycin
2 g	12
30 mg/kg (maximum 1 g per dose)	12
Levofloxacin
Adult (child >50 kg)	750 (500–750) mg	24	PO/IV
Child <50 kg and ≥6 months of age	16 mg/kg (maximum, 250 mg/ dose)	12	PO/IV
Ciprofloxacin
1500 mg	12
1200 mg	8
30–45 mg/kg (maximum, 500 mg/dose)	8–12
20–30 mg/kg (maximum, 400 mg/dose)	8–12
Moxifloxacin
Adult	400 mg	24	PO/IV
Doxycycline
200 mg (200 mg loading dose)	12
4.4 mg/kg (maximum, 100 mg/ dose, 4.4 mg/kg loading dose)	12
Tetracycline
Adult	2 g	6	PO/IV
Child >8 y	40–50 mg/kg	6	PO/IV
Chloramphenicol
50–100 mg/kg	6
50–100 mg/kg (maximum, 4 g)	6

TABLE 176-3 Guidelines for Plague Prophylaxis DRUG Doxycycline Adult Child ≥8 y¶

Harrison's 22e, p.1347

DRUG	DAILY DOSE	DOSING INTERVAL, h	ROUTE
Doxycycline
Adult	200 mg	12 or 24	PO
Child ≥8 y	≥45 kg: adult dose	12	PO
	≤45 kg: 4.4 mg/kg (maximum, 200 mg)	12	PO
Tetracycline
2 g	6 or 12
40 mg/kg (maximum 500 mg dose)	6 or 12
Levofloxacin
Adult and child >50 kg	500–750 mg	24	PO
Child <50 kg and ≥6 months of age	16 mg/kg (maximum, 250 mg/dose)	12	PO
Ciprofloxacin
1–1.5 g	12
30 mg/kg (maximum 750 mg dose)	12