Clinical Management and Sampling

Diagnosis and collection of samples

The first indication of a deliberate release via aerosol will be a cluster of acute, severe, flu-like illness with respiratory symptoms and unusual epidemiological features eg occurring in previously healthy young adults.

Type B strains released into water or food would probably present as a typhoidal illness or stomatitis/ pharyngitis/ tonsillitis with mucosal ulceration and tender cervical lymphadenopathy. In the highly unlikely event of release through direct contact eg via contaminated mail package, an ulceroglandular presentation would probably predominate.

Identification of F. tularensis in clinical specimens may be delayed for some time or missed altogether when procedures for routine microbiological screening of bacterial pathogens are followed, and it is unlikely that laboratory identification would be the initial event that alerted authorities to a deliberate release of this organism unless cysteine enriched media such as BCYE are used.

Precautions for sampling

The organism is most infectious by the inhalation route as fewer than 10 organisms of certain strains of type A F. tularensis may result in pulmonary tularemia. Infection may occur through the skin, mucous membranes, gastrointestinal tract, and lungs via infectious animal tissues or fluids, direct contact with or ingestion of contaminated water, food, or soil, and inhalation of infective aerosols. During the taking of clinical samples healthcare workers should observe universal contact precautions i.e., wearing gloves and plastic aprons followed by thorough handwashing. Healthcare workers should protect skin lesions with a water-proof dressing. Although person-to-person transmission has not been documented following casual contact, the use of the best available (highest efficiency) face and eye protection is recommended if infected secretions are likely to be aerosolised during sampling. A disposable surgical face mask will reduce the risk from large respiratory droplets, however, where available at least a medium efficiency FFP2 mask should be used. All laboratory work must be performed in a Class I safety cabinet in a containment level 3 facility. Exposure during examination of an open culture plate can cause infection and in several outbreaks the identity of the pathogen first became apparent after laboratory staff became infected after handling cultures on the open bench.

Samples to be taken from acutely ill humans

In suspected inhalational tularemia specimens of sputum, pharyngeal washings, fasting gastric aspirates, pleural fluid and blood may be culture positive for F. tularensis. Both radiometric and nonradiometric blood culture systems can detect F. tularensis, but subculture to cysteine rich medium such as BCYE is necessary for isolation. Other samples include exudates from lesions and biopsies of lymph nodes or cutaneous lesions. The procedure for transport of specimens to the laboratory is outlined here. The laboratory must be informed in advance. Chain of evidence documentation should also accompany all specimens; however in larger incidents this would only be required for several of the initial cases.

Post-mortem specimens

Samples may be taken from dead humans to assist diagnosis, including body fluids or tissues. However, full post-mortem examinations are strongly discouraged if tularemia is suspected.

Treatment

F. tualrensis is generally susceptible to a range of antibiotics. The antibiotic susceptibilities of 50 F.tularensis type B strains isolated from human patients and hares from Austria against 24 antibiotics were ascertained and all isolates were sensitive to tetracyclines, aminoglycosides, quinolones, chloramphenicol and rifampicin.

Gentamicin for 10 days is effective in the treatment of tularemia (see Table below) and is considered first line therapy. Gentamicin is administered as a 1 hour infusion and therefore antibiotic levels should be taken between 6 and 14 hours after the start of the first infusion to ascertain future dosing intervals in accordance with the Hartford nonogram. The Hartford nomogram suggests that at 6 hours the gentamicin level should be < 7.5 mg/litre, and at 14 hours =2 mg/litre. For all stages in between the Hartford nomogram can be used.

Streptomycin was regarded as the drug of choice for the treatment of non-meningeal tularemia in both adults and children but it is no longer widely available in the UK.

It is recognised that these agents are not routinely used as monotherapy in the treatment of acute febrile illnesses, including pneumonia. If tularemia is suspected but not confirmed microbiologically or serologically, an aminoglycoside should be added to an appropriate antibiotic regimen and not used as a single agent. Other antibiotics can be stopped when the identity of F. tularensis is confirmed and antibiotic susceptibility data available.

Ciprofloxacin and other fluoroquinolones have been used effectively to treat tularemia, although experience with these medications is somewhat limited. Ciprofloxacin and other fluoroquinolones are active in vitro and animal studies suggest that they are candidates for the treatment of pneumonic tularemia. Ciprofloxacin has been used successfully to treat a number of cases in both children and adults, including a large non-randomised study in Spain where 21 of 22 patients with predominantly ulceroglandular disease were cured. In one outbreak, ciprofloxacin showed a lower treatment failure rate than streptomycin or doxycycline. However, ciprofloxacin is not licensed for use in children or pregnant women.

Tetracycline and chloramphenicol are bacteriostatic against F. tularensis and if they are used in treatment at least 21 days therapy is required to reduce the chance of relapse. Due to the poor penetration of aminoglycosides into CSF, chloramphenicol may be added to gentamicin in the treatment of patients with clinical features of meningitis.

Recommended treatment for tularemia

	Antimicrobial Agent	Duration
Adults (including pregnant women)	Gentamicin (first choice in pregnancy*) 5mg/kg IM or IV once daily or Ciprofloxacin 400mg IV twice daily (change to oral 500mg bd when appropriate)	14 days
Children† >1month	Gentamicin 2.5 mg/kg IM or IV three times daily or Streptomycin 15 mg/kg IM twice daily (not to exceed 2g per day) or Ciprofloxacin 15mg/kg PO bd (maximum 500mg) - not to exceed 1g per day   Ciprofloxacin dose depends on age and weight, as a guide: newborn (up to 6 months)   100mg/day 1 year to <3 years="years" 200mg/day</p="200mg/day</p" /> 3 years to <5 years="years" 300mg/day</p="300mg/day</p" /> 5 years to <7 years="years" 400mg/day</p="400mg/day</p" /> 7 years to <12 years="years" 500mg/day</p="500mg/day</p" /> 12 years+(adult dose) 1000mg/day	10 days

* The Hartford nomogram for monitoring is not applicable to pregnant women due to their altered volume of distribution and a single daily dose may not be appropriate – multiple dosing may be needed (seek specialist advice).
† For children < 1month seek specialist advice re dosing of aminoglycosides.

 

Treatment of mass casualties

Treatment of large numbers of casualties following a deliberate release may warrant the use of oral ciprofloxacin and doxycycline. The risk of side effects from medication would not preclude their use in children, in such a situation. In a major incident information on how to access stocks of antibiotics for treatment or prophylaxis can be found on the Department of Health website at:

http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_081038

 

Infection control practice

Decontamination of exposed persons

The number of viable organisms that may be re-aerosolised following the handling of contaminated clothing of exposed individuals is probably low. However, even low numbers of organisms could potentially lead to infection in any person having contact. An incident specific risk assessment will be required.

In situations where the threat of exposure to F. tularensis exists, cleansing of skin and potentially contaminated fomites such as clothing, personal possessions or environmental surfaces should take place. Decontamination of exposed individuals should be include:

• Removal of contaminated clothing and possessions, which should be placed, with minimum agitation, in labelled and sealed double plastic bagsand stored until exposure to F. tularensis has been ruled out .
• Contaminated material must be incinerated or autoclaved.
• Instructing exposed persons to shower thoroughly with soap and water- appropriate facilities will be provided at the scene as necessary.

Attending personnel should wear full PPE including standard Universal Precautions when handling contaminated clothing and other fomites.

Isolation of patients

• Standard universal precautions including gloves, gowns and hand washing are recommended for patients with tularemia.
• Although person-to-person spread of F. tularensis has not been reported following casual contact, isolation of patients in a side room, or as a cohort on a ward, is recommended for pulmonary disease or where there is a danger of aerosolisation from lesions during sampling.
• All persons entering or leaving the room should wear the best available (highest efficiency) face and eye protection in addition to standard Universal Precautions when attending to isolated patients. Lesions should be covered with a waterproof dressing.

Protective clothing

Following an overt release of F. tularensis the area affected by primary aerosolisation will depend on the time and place of release. This exposed zone presents a high risk of infection, and anyone entering it should wear a biologically-resistant suit with outer gloves and boots (for example a CR1, PRPS or gas-tight suit) and a correctly fitting high-efficacy respirator of FFP3 standard AT ALL TIMES.

Healthcare workers will not normally be asked to enter this zone, however it is possible that they may be called into it to treat casualties, for example if an explosive device has accompanied the release of a biological agent. In this case the appropriate protective clothing should be worn.

Exposed persons will normally be moved from the exposed zone, through decontamination if necessary, and into a place of safety or holding area for medical assessment. Frontline workers involved in the decontamination of exposed individuals and handling of contaminated clothing and fomites should observe standard universal precautions – gloves, plastic aprons along with face masks and eye protection if splashing is likely. Hands should always be washed after the removal of gloves.

For healthcare workers involved in the management of hospitalised patients with tularemia Universal Precautions provide sufficient protection. Mortuary staff should use similar barrier protection.

Cleaning, disinfection and waste disposal

Normal procedures for standard isolation are appropriate. Contaminated environmental surfaces should be cleaned with hypochlorite solution (10,000 ppm available chlorine). NB: This should not be applied to body surfaces. Laundry and garments should be placed in plastic bags and launderedthroughahotcycle(>70ºC) when F. tularensis is confirmed.

Post-mortem

Autopsy
The risk of acquiring tularemia following contact with the body of a person who has died from the disease is minimal because, although there is no person-to-person transmission, there is evidence of autopsy transmission.

Autopsy examinations are strongly discouraged if tularemia infection is suspected, as the body fluids and tissues of a patient who has died of tularemia are likely to have F. tularensis bacteria present in them. If an autopsy is necessary expert advice must be sought from the HPA. The Pathologist must be informed of the known or suspected diagnosis. Standard precautions for post-mortem examinations on patients infected with Containment Level 3 organisms are appropriate. Instruments should be autoclaved.

Similarly, body preparation should be carried out with normal control of infection procedures. Standard precautions for the disposal of bodies infected with Containment Level 3 pathogens should be observed, and the undertaker should be informed. Cremation is the preferred method of disposal for the deceased. Embalming of bodies should not be undertaken because the body fluids are likely to contain large numbers of the causative bacteria and therefore the process of embalming exposes the embalmer to an unacceptable risk.

Pacemaker removal is permitted. Pacemaker should be treated with hypochlorite solution (10,000 ppm available chlorine), bagged and disposed of appropriately (not by incineration).

Last reviewed: 18 May 2010