# Presentation: 877944

## Bioterrorism Agents – PlagueLesson 5

- Medical Management

## Objectives

- Management of suspect and confirmed cases
- Medications – Controlled Situation
- Medications – Mass Casualty
- Infection Control

**Notes:**
In this lesson the treatment of plague cases is covered, as well as infection control issues. At the end of this lesson you should be able to:

 Describe the medical management of suspected and confirmed plague cases
 List the medication options available for treating plague in a controlled situation
 List the medication options available for treating plague in a mass casualty situation
 Describe infection control procedures for plague patients

## Overview

- Prompt treatment required
*Y. pestis* – enterobacteriaceae
- Responsive to most antimicrobials

**Notes:**
Overview
Plague is an acute, rapidly severe, and potentially fatal illness unless treated promptly and correctly. Complications of infection may require intensive medical support services. 
Yersinia pestis belongs to the bacterial family Enterobacteriaceae, and is responsive to most antimicrobials active against this group of bacteria.

## Overview

- Aerosol exposure – plague pneumonia
- Medical Management
- Prompt antimicrobial administration
- Respiratory droplet precautions
- Intensive respiratory support
- Management of consequences

**Notes:**
Overview 
Aerosol exposures are considered likely to result in cases of severe plague pneumonia and consequent septicemia. 
The medical management of pneumonic plague requires 
prompt antimicrobial administration, 
isolation using respiratory droplet precautions, 
intensive respiratory support, 
as well as management of septicemia, endotoxemia, and consequences of the acute inflammatory response syndrome.

## Treatment Issues

- Clinical improvement 36 to 48 hours, if responding to treatment
- Cannot recover *Y. pestis* after 36 hours of treatment
- All US strains have been sensitive to current treatments, to date

**Notes:**
Overview
Patients responding to treatment typically have a lower temperature and show other signs of clinical improvement within 36 to 48 hours of the initiation of treatment. 
In patients with pneumonic plague, Y. pestis is usually not able to be cultured from respiratory secretions after 36 hours of treatment. So every effort should be made to obtain laboratory specimens before treatment is begun. 
To date, all United States Y. pestis strains tested have been sensitive to all antimicrobials recommended for plague treatment. 
The antimicrobial treatment and prophylaxis regimens recommended here are based on known antimicrobial susceptibilities and on manufacturers’ recommendations for treating severe infections. 

## Treatment in Bioterrorism

- BT Plague – High suspicion of resistance
- Perform testing rapidly
- Watch for Health Alerts
- Treatment/Prophylaxis recommendations may change

**Notes:**
Overview
If Y. pestis is used as an agent of bioterrorism, there should be a high index of suspicion of antimicrobial resistance. 
In threat circumstances, susceptibility testing should be rapidly performed on organisms isolated from the environment and from clinical specimens, and responses to treatment closely monitored. 
Public health authorities will issue Health Alerts to inform clinicians of the results of susceptibility testing as soon as they are known. The recommendations for treatment and prophylaxis might have to be changed, depending on what is found.

## Streptomycin

- Historically preferred
- FDA-approved
- Not widely and immediately available
- Floroquinolones?

**Notes:**
Overview
Streptomycin has historically been the preferred treatment for plague and is FDA-approved for this purpose. 
Streptomycin may not be widely and immediately available. 
The aminoglycosides, tetracyclines, and chloramphenicol are antimicrobials routinely used to treat plague. 
Among newer classes of antimicrobials, Y. pestis is susceptible to fluoroquinolones in vitro, and fluoroquinolones are efficacious in treating experimental plague in animals.

## Treating an Outbreak

- Gentamicin – IND protocol
- Contained Casualty – parenteral antimicrobial therapy
- Mass Casualty – oral therapy

**Notes:**
Overview
In the US, gentamicin for plague is an off-label, non-FDA-approved use and therefore must be given under an IND protocol. CDC has an investigational new drug for this purpose. 
Should antimicrobial susceptibility testing or poor clinical response indicate antimicrobial resistance, substitution would be required. 
In a contained casualty situation, when a modest number of patients require treatment, parenteral antimicrobial therapy is recommended. 
In a mass casualty situation, where large numbers of patients require treatment (not allowing full individual patient care), oral therapy may be recommended as an alternative to parenteral therapy. 

## Recommended Plague TreatmentNotes on Options

- Based on consensus of working group and not FDA
- Choose one agent.
- Treatment for 10 days
- Substitute oral therapy when condition improves

**Notes:**
These are consensus recommendations of the Working Group on Civilian Biodefense and are not necessarily approved by the U.S. Food and Drug Administration. 

   One antimicrobial agent should be selected. Therapy should continue for 10 days. Oral therapy should be substituted when the patient's condition improves. 

## Recommended Plague TreatmentContained Casualty - Adults

| Preferred |  |
| --- | --- |
| Streptomycin | 1g IM BID |
| Gentamicin | 5 mg/kg IM or IV daily OR 
2 mg/kg loading with 1.7 mg/kg IM or IV TID |
| Alternative |  |
| Doxycycline | 100mg IV BID or 200mg IV |
| Ciprofloxacin | 400mg IV BID |
| Chloramphenicol | 25 mg/kg IV QID |

**Notes:**
Contained Casualty Setting

Adults
Preferred choices: 
  Streptomycin - 1g IM twice daily
  Gentamicin - 5 mg/kg IM or IV once daily or 2 mg/kg loading dose followed by 1.7 mg/kg IM or IV three times daily

Alternative choices: 
  Doxycycline - 100 mg IV twice daily or 200 mg IV once daily 
  Ciprofloxacin - 400 mg IV twice daily
  Chloramphenicol - 25 mg/kg IV 4 times daily§

The treatment regimen for pregnant women and immunocompromised adults is the same as other adults.  

However, it is important to note when dealing with pregnant women that aminoglycosides can cause fetal ototoxicity when administered to pregnant women.  Benefits may, however, outweigh the risks when treating serious infections.  You should also be reminded that tetracyclines can cause damage to fetal teeth and bones when administered to pregnant women.

## Recommended Plague TreatmentContained Casualty - Children

| Preferred |  |
| --- | --- |
| Streptomycin | 15 mg/kg IM BID (max 2g daily) |
| Gentamicin | 2.5 mg/kg IM or IV daily TID |
| Alternative |  |
| Doxycycline | 45kg - 100mg IV BID or 200mg IV |
| Ciprofloxacin | 15 mg/kg BID |
| Chloramphenicol | 25 mg/kg IV QID |

**Notes:**
Children
Preferred choices: 
  Streptomycin - 15 mg/kg IM twice daily (maximum daily dose 2 g) 
  Gentamicin -  2.5 mg/kg IM or IV 3 times daily

Alternative choices: 
  Doxycycline - If >= 45 kg, give adult dosage If < 45 kg, give 2.2 mg/kg IV twice daily (maximum 200 mg/dl) 
NOTE:  In 1991, the American Academy of Pediatrics amended its recommendation to allow treatment of young children with tetracyclines for serious infections for which doxycycline may be indicated.  Doxycycline is preferred for its twice daily dosing and low incidence of gastrointestinal side effects.
  Ciprofloxacin - 15 mg/kg IV twice daily
  Chloramphenicol - 25 mg/kg IV 4 times daily

Immunocompromised children can receive the same treatment regimen.

## Recommended Plague TreatmentMass Casualty - Adults

| Preferred |  |
| --- | --- |
| Doxycycline | 100 mg PO BID |
| Ciprofloxacin | 500 mg PO BID |
| Alternative |  |
| Chloramphenicol | 25 mg/kg PO QID |

**Notes:**
Mass Casualty Setting
Adults
Preferred choices: 
  Doxycycline - 100 mg orally twice daily
  Ciprofloxacin - 500 mg orally twice daily

Alternative choices: 
  Chloramphenicol - 25 mg/kg orally 4 times daily

The same would be recommended for pregnant women and immunocompromised adults.

## Recommended Plague TreatmentChildren – Mass Casualty

| Preferred |  |
| --- | --- |
| Doxycycline | 45kg - 100 mg PO BID
<45kg – 2.2mg/kg PO BID |
| Ciprofloxacin | 20 mg/kg PO BID |
| Alternative |  |
| Chloramphenicol | 25 mg/kg IV QID |

**Notes:**
Children
Preferred choices: 
  Doxycycline -  If >=45kg give adult dosage If <45 kg then give 2.2 mg/kg orally twice daily
  Ciprofloxacin - 20 mg/kg orally twice daily

Alternative choices: 
  Chloramphenicol - 25 mg/kg orally 4 times daily

## Streptomycin preferred, but hard to find
Frequency at discretion of clinician
Initial loading dose 2 mg/kg standard when given three times per day
Not FDA-approved
Refer to package insert re renal insufficiency

- Frequency at discretion of clinician
- Initial loading dose 2 mg/kg standard when given three times per day
- Not FDA-approved
- Refer to package insert re renal insufficiency

- Recommended Plague TreatmentNotes on Gentamicin

**Notes:**
[1] Historic treatment of choice for plague is streptomycin.  Streptomycin can be difficult to obtain; therefore, gentamicin is recommended and is included in the Strategic National Stockpile.  Oral therapy should be substituted when clinically indicated.
[1] The frequency of administration is left up to the discretion of the clinician.  The manufacturers recommend that the daily dose be given in equally divided doses at 8-hour intervals; however, current evidence suggests that once-daily dosing of aminoglycosides is at least as effective as, and may be less toxic than, conventional dosing regimens employing multiple daily doses of the drugs.
[1] An initial loading dose of 2 mg/kg body weight is standard medical practice when gentamicin is given as three doses per day.
[1] Not a US Food and Drug Administration (FDA)-approved use.
[1] Refer to package insert to adjust dose in the event of renal insufficiency.

## Recommended Plague TreatmentNotes on Children

- Gentamicin may be efficacious, but not widely accepted clinical practice
- Neonates up to 1 wk – 2.5 mg/kg IV BID
- Can substitute other fluoroquinolones
- Ciprofloxacin – dosage no more than 1 g/d, concentrations between 5 – 20 μg/ml
- Chloramphenicol –dosage no more than 4g/d.  No one younger than 2 years.

**Notes:**
Evidence suggests that gentamicin, 5 mg/kg IM or IV once daily, would be efficacious in children, although this is not yet widely accepted clinical practice.

Neonates up to 1 week of age and premature infants should receive gentamicin, 2.5 mg/kg IV twice a day.
Other fluoroquinolones can be substituted at doses appropriate for age. 
   Ciprofloxacin dosage should not exceed 1 g/d in children. Concentration should be maintained between 5 and 20 μg/mL. Concentrations greater than 25 μl/mL can cause reversible bone marrow suppression.
   In children, ciprofloxacin dose should not exceed 1g/d, and chloramphenicol should not exceed 4g/d.
  Children younger then 2 years should not receive chloramphenicol
  In neonates, gentamicin-loading dose of 4 mg/kg should be given initially.
   Duration of treatment of plague in mass casualty setting is 10 days. Duration of postexposure prophylaxis to prevent plague infection is 7 days.
  Tetracycline could be substituted for doxycycline in children.

## Plague Infection Control Precautions

- Isolation for 48 hours of antibiotic treatment or until clinical improvement

| Bubonic | Standard |
| --- | --- |
| Pneumonic | Standard and Respiratory |
| Septicemic | Standard |
| Suspect | Respiratory and Isolation |

**Notes:**
Infection Control
The use of standard precautions is appropriate for managing plague patients who do not have respiratory infections. 
In past epidemics, patient-to-patient transmission only seemed to occur after close contact, often for prolonged periods, with a patient that coughed bloody sputum. It is extremely rare for patients in the early stage of pneumonic plague to transmit the infection to others. 
Bubonic: Standard and contact precautions if any open wounds. 
Pneumonic: Standard and respiratory droplet precautions. (Note: Available evidence indicates that person-to-person spread of pneumonic plague is via respiratory droplets, not fine aerosols or droplet nuclei.) 
Septicemic: Standard precautions. 
Pneumonic plague patients are no longer infective after 24 to 48 hours of antibiotic treatment, because the sputum no longer contains live bacilli. However, they may still be ill and continue demonstrating signs of pneumonia.  

## Plague Infection Control

- Cohort and Droplet precautions if no isolation available
- Isolation of contacts may increase in importance for outbreak control
- Corpses – Standard Precautions

**Notes:**
Infection Control 
When individual isolation of suspected plague patients is not possible, they should be cohorted away from other hospital patients, and managed under respiratory droplet precautions until no longer considered to be contagious. 
Although quick diagnosis and appropriate antibiotic treatment is imperative in preventing the spread of disease throughout the community, isolation of contacts and/or quarantine may increase in importance for outbreak control. 
The bodies of persons who have died from plague should be handled with standard infection control precautions

## Occupational ExposureHospital and Laboratory

- Skin Exposures – Nonabrasive soap and water, standard workplace exposure policy
- Eye Exposures – Flush with water or eye wash solution x 15 minutes
- Post-Exposure doxycycline or ciprofloxacin x 7 days
- Laboratory – avoid aerosolization

**Notes:**
Occupational Exposures – Hospital and Laboratory
Medical staff or laboratory workers accidentally exposed to infectious materials via needle sticks, cuts, or abrasions should immediately wash the area with a nonabrasive soap and water and follow the standard policy of their institution regarding workplace exposures. 
When eye exposure occurs, the eye should be flushed with copious amounts of water or eye wash solution for at least 15 minutes. 
In addition, postexposure antimicrobial prophylaxis with doxycycline or ciprofloxacin should be started immediately and continued for 7 days. 
Laboratory workers who handle cultures should be alerted to the possibility of Y. pestis and take precautions to avoid aerosolization of cultures or other infectious materials. 

## Occupational ExposuresLaboratory Spills

- Cover in absorbent materials
- 1:100 bleach x 30 minutes
- Wipe with absorbent materials soaked in 1:100 bleach
- Clean with nonabrasive soap and water
- Dispose all materials biohazard
- BSL2 for all suspect materials

**Notes:**
Occupational Exposures – Laboratory Spills
Spills of potentially contaminated materials should be immediately covered with absorbent materials and disinfected with 10% bleach for 30 minutes. 
Surfaces should then be wiped with absorbent towels that have also been soaked in 10% bleach. 
The areas should then be cleaned with nonabrasive soap and water. 
All materials used in the cleanup should be disposed of as biohazardous waste. 
Biosafety Level 2 guidelines should be used to handle all suspect material. 

## Occupational ExposuresField Workers

- Incident Commander assigns PPE levels
- Minimum of Level B PPE
- Tyvek outer clothing
- Gloves
- Booties
- Positive pressure HEPA filtered respirators
- All PPE decontaminated or disposed of as biohazardous waste

**Notes:**
Occupational Exposures – Field Workers
Field workers should follow the personal protective equipment (PPE) requirements provided to them by the incident commander. 
A minimum of Level B PPE should be used for fieldwork posing possible infective exposure. 
Tyvek outer clothing 
Gloves 
Booties 
Positive-pressure HEPA-filtered respirators 
All PPE must be decontaminated or disposed of as biohazardous waste. 

## Review Questions - PlagueLesson 5

- Medical Management

## Plague Review QuestionsLesson 5, Question 1

- News report – 75 cases of plague in area
- Ambulances arriving at ER
- Exposed to intentional plague bacteria release
- Which antibiotic would you choose?

**Notes:**
The morning news carries a breaking news story that a report has been received in the newsroom of about 75 cases of plague in people in your area.  Within minutes, ambulances begin arriving at your emergency room with people who are believed to have been exposed to an intentional release of plague bacteria.  After evaluation, you need to make a decision about which antibiotic to prescribe.  You would choose:  

## Plague Review QuestionsLesson 5, Question 1

- Which antibiotic would you choose?
- Streptomycin – 1g IM BID
- Doxycycline – 100 mg PO BID
- Gentamicin – 5 mg/kg IM or IV daily
- Any of the above

**Notes:**
You have people who have been exposed to an intentional release of plague bacteria.  What antibiotic would you choose?

A.  Streptomycin 1g IM twice daily
B. Doxycycline 100 mg orally twice daily
C. Gentamicin 5 mg/kg IM or IV once daily
D. Any of the above

## Plague Review QuestionsLesson 5, Question 1

- Which antibiotic would you choose?
- B. Doxycycline – 100 mg PO BID

**Notes:**
Which antibiotic would you choose in a mass casualty situation?  The best answer is B:  Doxycycline 100mg given orally twice per day.  

Any of the listed antibiotics are used to treat plague.  However, in the event of a mass casualty setting (where many persons have been exposed to plague), CDC recommends an investigational new drug protocol.  This protocol is based on published studies in humans and animal models, in vitro susceptibility testing, and antimicrobial safety.  Oral doxycycline would be preferable for adults, children, and pregnant women in this setting, with therapy continuing for 10 days.

IM and IV drugs may be too time-consuming to administer when patient numbers are high.

## Plague Review QuestionsLesson 5, Question 2

- Suspect pneumonic plague patient
- What precautions would you take immediately?

**Notes:**
You suspect that you have a patient with   pneumonic plague.  You would immediately take the following precautions:

## Plague Review QuestionsLesson 5, Question 2

- What precautions would you take immediately?
- Standard precautions
- Standard and contact precautions
- Standard and respiratory droplet precautions
- Negative pressure room

**Notes:**
What precautions would you immediately initiate with a suspect plague patient?

 Standard precautions
B. Standard and contact precautions
C. Standard and respiratory droplet precautions 
D. Quickly get the patient to a negative pressure room

## Plague Review QuestionsLesson 5, Question 2

- What precautions would you take immediately?
- C.  Standard and respiratory droplet precautions

**Notes:**
The best answer is C:  Standard and respiratory droplet precautions

Evidence shows that person-to-person transmission of pneumonic plague occurs via respiratory droplets.  Bubonic plague and septicemic plague would require the use of standard precautions; contact precautions would be included in bubonic plague if there were open wounds.

## Plague Review QuestionsLesson 5, Question 3

- Pneumonia patient
- Lab unable to rule out plague
- What medication do you prescribe for a controlled casualty situation?

**Notes:**
Your laboratory has been unable to rule out plague in your pneumonia patient.  In a controlled casualty situation, what medication would you prescribe for the patient?

## Plague Review QuestionsLesson 5, Question 3

- What medication do you prescribe for a controlled casualty situation?
- Penicillin
- Gentamicin
- Zithromicin
- Biaxin

**Notes:**
What antibiotic would you prescribe in a single plague patient?

A.  Penicillin
B. Gentamicin
C. Zithromicin
D. Biaxin

## Plague Review QuestionsLesson 5, Question 3

- What medication do you prescribe for a controlled casualty situation?
- B.  Gentamicin

**Notes:**
Gentamicin is the preferred treatment and allowed for on-label use by the FDA.

While it is possible that other antibiotics could manage plague infection, Gentamicin is the preferred treatment and allowed as an on-label use by the FDA.

## Plague Review QuestionsLesson 5, Question 4

- Pneumonic plague patient
- Gentamicin x 48 hours
- How would you expect the patient to progress?

**Notes:**
Your pneumonic plague patient has been on gentamicin for 48 hours.  At this point, how should you expect the patient to progress?

## Plague Review QuestionsLesson 5, Question 4

- How would you expect the patient to progress?
- Spike in temperature, toxic
- Still infectious, remain in isolation
- Showing signs of clinical improvement
- Signs of inflammatory response

**Notes:**
How would you expect a pneumonic plague patient to progress after 48 hours of gentamicin therapy?

A.  Patient will have a spike in temperature and appear toxic for a few more days
B. Patient will still be infectious and should remain in respiratory isolation
C. Patient should be showing signs of clinical improvement
D. Patient will display signs of an inflammatory response

## Plague Review QuestionsLesson 5, Question 4

- How would you expect the patient to progress?
- C.  Showing signs of clinical improvement

**Notes:**
The best answer is C.  After 36 to 48 hours on the appropriate antibiotic therapy, the patient should begin to show signs of clinical improvement.  At this point in time, they should no longer be infectious and can be taken off of respiratory isolation.