Francisella tularensis

Zoonontic infection carried on rodents and rabbits and transmitted by biting insects
Presentation depends on route of entry: (ulcero)glandular, oculoglandular, pharyngeal, typhoidal, or pneumonic
Treatment is streptomycin

Background

A fastidious Gram-negative coccobacillus
Multiple subspecies, including tularensis, holarctica, novocida, mediasiatica, which are further subdivided into clades, and related species Francisella philomiragia and Francisella hispaniensis
Subspecies of importance to humans include:
- Subspecies tularensis (type A strains)
  - Found in North America and rarely Europe
  - Two major clades (AI and AII) and four subclades (AIa, AIb, AIIa, and AIIb)
  - Overall the subspecies is the most virulent subspecies, and specifically the AIb subclade is the most virulent strain
- Subspecies holarctica (type B strains)
  - Found in the entire northern hemisphere as well as Australia
  - Four major clades (B4 in North America, B6 in Western Europe, B12 in Eastern Europe and Central Asia, and B16 in Japan and other areas in Eastern Asia) and a number of subclades
- Subspecies novicida
  - Rare cause of disease in humans, usually in immunocompromised hosts, and presents with bacteremia rather than tularemia
- Subspecies mediasiatica does not cause disease in humans

Zoonotic infection whose main animal reservoirs are rodents and rabbits
- In North America, the most important reservoirs are Sylvilagus species (especially Sylvilagus nuttalii, the cottontail rabbit) and Lepus species lagomorphs (rabbits), and a number of rodents including voles, squirrels, muskrats, and beavers
- In Europe, the reservoirs include voles, hamsters, mice, and hares
Essentially worldwide Northern Hemisphere distribution, especially in the US, Japan, Russia, and Scandinavian countries
Transmission:
- Vector-borne
  - In North America, by Amblyomma americanum ticks, Dermacentor variabilis ticks, Dermacentor andersoni ticks, Chrysops discalis deer flies
  - In Europe, Aedes cinereus and Ochlerotatus exrucians mosquitoes are more important, as well as Chrysops relictus deer flies and Haematopota pluvialis horse flies
- Direct contact with animal products, including skinning, dressing, and eating wild game
  - Viable in carcasses and dust for up to 136 days
- Inhalation of aerosolized vectors (e.g. lawn-mowing), contact with contaminated water or mud, and animal bites of animals that have killed infected reservoir hosts (e.g. cats killing rodents)

Infectious dose depends on route, but is as low as 10 to 50 organisms when injected intradermally or inhaled (or several orders of magnitude higher if ingested)
TLR4 has less affinity for its LPS compared to other bacteria
Capsule inhibits IgM and complement C3
- Capsule-deficient strains are both less immunogenic and less virulent
Facultative intracellular growth
- Can infect and persist within erythrocytes, providing protection against aminoglycosides

Incubation period of 3 to 5 days (range 1 to 21 days)
The first symptom is usually a papule at the site of inoculation that develops into an ulcer over 1 to 2 days, but this may go unnoticed
This is followed by fever which likely corresponds to initial lymphohematogenous dissemination
- Other common symptoms include chills, headache, malaise, anorexia, and fatigue
- May also have cough, myalgias, chest discomfort, vomiting, sore throat, abdominal pain, and diarrhea
- May have a relative bradycardia (more common in US than Europe)
These symptoms may remit and relapse, presenting as a subacute relapsing fever over weeks, with associated weight loss, deconditioning, and lymphadenopathy
Ulceroglandular: ulcer develops at site of inoculation with tender lymphadenopathy and systemic symptoms
Glandular: ulcer is undetectable or healed, only lymphadenopathy and systemic illness remains
Oculoglandular: entry through the conjuctiva
Pharyngeal: entry through the oropharynx, with exudative pharyngitis/tonsillitis
Typhoidal: febrile illness without lymphadenopathy or ulcer, sometimes with diarrhea; patient often has an underlying chronic disease
Pneumonic: direct inhalation, often from sheep shearing, landscaping, and microbiology laboratory work

Culture
- Grows slowly on standard culture media, needs cystine-rich media (e.g. chocolate agar, BHI, or cystine media)
- Looks bacillary in logarithmic growth phase (small Gram-negative rod), slow-growing only on chocolate agar
Serology (EIA) can be used in the right context
PCR

For severe disease, streptomycin 10 mg/kg (max 1 g) IM q12h for 7 to 10 days
- Alternatives include gentamicin or amikacin
For mild to moderate disease, alternatives include:
- Doxycycline 100 mg po bid for 14 to 21 days
- Ciprofloxacin 500 mg po bid for 10 to 14 days
For meningitis, use an aminoglycoside (as above) plus either IV ciprofloxacin, doxycycline, or chloramphenicol for 14 to 21 days
- Aminoglycosides have poor CNS penetration

This is a biosafety risk group 3 organism
Should be suspected with any slowly-growing, small, and poorly-staining Gram-negative coccobacillus is isolated on chocolate agar but not blood agar
Automated laboratory identification systems should not be used, because the risk of aerosol generation
Commonly misidentified by automated methods as Haemophilus or Aggregatibacter species