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Yersinia pestis (Plague) Attack
CHAPTER
125
Yersinia pestis (Plague) Attack Kimberly A. Stanford and Jonathan Harris Valente
DESCRIPTION OF EVENT A bioterrorism event leading to multiple cases of the plague would likely result from airborne dispersal of a weaponized form of Yersinia pestis and would cause a pulmonary variant of the plague called pneumonic plague.1 Outbreaks of pneumonic plague have also been reported following natural disasters, such as after the 1994 earthquake in Maharashtra, India, and in war-torn regions, such as the Congo, as recently as the first decade of the twenty-first century.2 During World War II, in two separate incidents, the Japanese dropped clay pots filled with Y. pestis-contaminated rice and fleas over the Chinese cities of Shusien, in Chekiang province, and Changteh, in Hunan province. This tactic led to outbreaks of bubonic plague.3,4 However, it would not be the optimal way for terrorists to spread the plague because bubonic plague requires a bite from a flea. In addition, bubonic plague is not spread directly from person to person as is the pneumonic form. Pneumonic plague may occur as a secondary pneumonia due to hematogenous spread from bubonic plague. This is the most common form of naturally occurring pneumonic plague. Primary pneumonic plague occurs after inhalation of aerosolized Y. pestis bacilli, either from person-to-person transmission or via an intentional attack. Pneumonic plague is rapidly progressive, and it can spread from person to person via aerosolized droplets. The incubation period for pneumonic plague (1 to 6 days) is shorter than that of the bubonic form (2 to 8 days).5,6 Control of the disease would be complex because affected people without knowledge of the exposure could spread disease by travel to other regions.7–9 Pneumonic plague presents clinically as a rapidly progressive respiratory syndrome that is often associated with fever, cough, shortness of breath, chest pain, hemoptysis, malaise, myalgia, nausea and vomiting, sputum or blood cultures with gram-negative rods, and radiographic findings of pneumonia. Chest roentgenograms of patients with pneumonic plague usually show patchy bronchopneumonic infiltrates as well as segmental or lobar consolidation with or without confluence. They may show cavitary lesions or bilateral diffuse infiltrates characteristic of acute respiratory distress syndrome.10 Time from onset of symptoms to fulminant disease is generally less than 24 hours, rapidly progressing to disseminated intravascular coagulation (DIC), circulatory collapse, and respiratory failure.11 It has been estimated that if 50 kg of weaponized Y. pestis were released as an aerosol over a city of 5 million people, pneumonic plague could occur in as many as 150,000 persons, 36,000 of whom would be expected to die.12
PRE-INCIDENT ACTIONS An intentional plague outbreak should be considered one of the most likely bioterrorism scenarios for which emergency providers need to
prepare. Pneumonic plague would most likely occur naturally as a complication of bubonic plague in the setting of a major bubonic plague outbreak.13 Warning the public to avoid contact with dead animals, especially rodents such as marmots, is an important preventive measure following a natural disaster such as a large earthquake.14 Y. pestis is not stable in the environment, and it is readily destroyed by drying and sunlight exposure. If Y. pestis were released into the air in a bioterrorism attack, it would likely survive for less than an hour. Because of these factors, preparation for environmental decontamination is less important than it would be in other similar attacks, such as with anthrax.8,9,12 No vaccine is currently available. The U.S. manufactured vaccine, a killed whole-cell vaccine (Greer), was discontinued in 1999 because of significant adverse effects and because it was not protective for the pneumonic form of the plague. Subunit vaccines based on rF1V and LcrV antigens are currently undergoing clinical trials, and these are the most promising prospects, but efficacy against pneumonic plague, specifically, is unclear. Live attenuated vaccine is likely the best option in this regard, but it carries the risk of reversion to virulence, limiting its utility.15 There are no early-warning systems for the detection of Y. pestis if an aerosolized form were dispersed. A real-time PCR has been developed with the potential for identification of Y. pestis in less than 5 hours, from blood or sputum, including identification of specific strains such as ciprofloxacin-resistant.16–18 However, newly engineered strains for use as bioterrorist agents might not be detected by this assay, and thus culture and biochemical identification must still be used for confirmation.
POST-INCIDENT ACTIONS All cases of pneumonic plague should be considered terrorism-related until proven otherwise. Hospital infection control officers and local and state, national health, and law enforcement officials should be notified immediately of any suspected cases of the plague. The risk for reaerosolization of Y. pestis from the contaminated clothing of exposed persons is low. Under ideal conditions, Y. pestis can survive in the environment for about 1 hour, and since patients will present with symptoms after 24 hours, there is no need for routine decontamination. In situations where there may have been recent, gross exposure to Y. pestis, decontamination of skin and potentially contaminated fomites (e.g., clothing or environmental surfaces) may be considered to reduce the risk of cutaneous or bubonic forms of the disease. The plan for decontaminating patients may include several steps. Patients should be instructed to remove contaminated clothing. Clothing should be stored in labeled, plastic bags and gently handled to avoid dispersal of Y. pestis. Patients should be instructed to shower thoroughly with soap and water. Environmental surface decontamination may be performed using an Environmental
705
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SECTION XII
Biological Events, Part 1: Bacterial Agents
Protection Agency-registered, facility-approved sporicidal/germicidal agent or a 0.5% hypochlorite solution (one part household bleach added to nine parts water).1,19,20 In addition to standard decontamination procedures, chlorine dioxide gas has been shown to rapidly deactivate almost 100% of Y. pestis in a hospital environment, but further studies are needed regarding safe usage.21 In its natural form, pneumonic plague is transmitted person to person via large droplets (not via fine-particle aerosol), and it requires close personal contact (2 m or less) for effective transmission.5,22,23 Patients with symptoms suggestive of pneumonic plague should be isolated using droplet precautions in addition to standard precautions. Patients with suspected pneumonic plague should be placed in a private room when possible. It is appropriate to cohort symptomatic patients with similar symptoms and the same presumptive diagnosis (i.e., pneumonic plague) when private rooms are not available. Maintain spatial separation of at least 3 feet between infected patients and others when
TABLE 125-1
Recommendations for Antimicrobial Treatment of Pneumonic Plague* PATIENT CATEGORY
Loading dose followed
MEDICAL TREATMENT OF CASUALTIES Specific antibiotic treatment must be initiated within 24 hours after symptom onset, otherwise pneumonic plague is nearly uniformly
TABLE 125-1
Recommendations for Antimicrobial Treatment of Pneumonic Plague—cont'd PATIENT CATEGORY
RECOMMENDED THERAPY
Childrenk
Preferred choice Doxycycline†† If <45 kg, 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},** Preferred choices Doxycycline, 100 mg orally twice daily†† Ciprofloxacin, 500 mg orally twice daily Alternative choices Chloramphenicol, 25 mg/kg orally 4 times daily},**
RECOMMENDED THERAPY
Contained Casualty Setting Adults Preferred choices Streptomycin, 1 g 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 3 times daily† Alternative choices (first choice for postexposure prophylaxis) 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} k 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/d) Ciprofloxacin, 15 mg/kg IV twice daily{ Chloramphenicol, 25 mg/kg IV 4 times daily} Pregnant women}
cohorting is not possible. Avoid placement of patients requiring droplet precautions in the same room with an immunocompromised patient. Special air handling is not necessary, and doors may remain open. Patient transport should be limited to essential medical purposes. When transport is necessary, minimize dispersal of droplets by placing a surgical-type mask on the patient. Isolation precautions should be continued for 2 days after initiation of antibiotics and until some clinical improvement occurs in patients with pneumonic plague.9
Preferred choice Gentamicin, 5 mg/kg IM or IV once daily or 2 mg/kg By 1.7 mg/kg IM or IV 3 times daily† Alternative choices Doxycycline, 100 mg IV twice daily or 200 mg IV once daily Ciprofloxacin, 400 mg IV twice daily{
Mass Casualty Setting and Postexposure Prophylaxis# Adults Preferred choices Doxycycline, 100 mg orally twice daily†† Ciprofloxacin, 500 mg orally twice daily{ Alternative choice Chloramphenicol, 25 mg/kg orally 4 times daily},**
Pregnant women}
*These are consensus recommendations of the Working Group on Civilian Biodefense and are not necessarily approved by the Food and Drug Administration. One antimicrobial agent should be selected. Therapy should be continued for 10 days. Oral therapy should be substituted when patient’s condition improves. IM indicates intramuscularly; IV, intravenously. † Aminoglycosides must be adjusted according to renal function. Evidence suggests that gentamicin, 5 mg/kg IM or IV once daily, would be efficacious in children, although this is not yet widely accepted in clinical practice. Neonates up to 1 week of age and premature infants should receive gentamicin, 2.5 mg/kg IV twice daily. { 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 μg/mL can cause reversible bone marrow suppression.24,25 k Refer to “Management of Special Groups” for details. In children, ciprofloxacin dose should not exceed 1 g/d, chloramphenicol should not exceed 4 g/d. Children younger than 2 years should not receive chloramphenicol. } In neonates, gentamicin loading dose of 4 mg/kg should be given initially.26 # Duration of treatment of plague in mass casualty setting is 10 days. Duration of postexposure prophylaxis to prevent plague infection is 7 days. **Children younger than 2 years should not receive chloramphenicol. Oral formulation available only outside the United States. †† Tetracycline could be substituted for doxycycline. (From Inglesby TV, et al. Consensus Statement: Plague as a Biological Weapon: Medical & Public Health Management. JAMA. 2000;283[17]: 2281-90.)
CHAPTER 125 Yersinia pestis (Plague) Attack fatal.7,9 Table 125-1 shows the Working Group on Civilian Biodefense’s antibiotic recommendations for pneumonic plague.9 These consensusbased recommendations cover contained exposures, mass casualty exposures, and postexposure prophylaxis. They are based on the best available evidence. However, it should be noted that there is a lack of published trials in treating plague in humans, and a limited number of studies in animals. A number of possible therapeutic regimens for treating plague have not been prospectively studied or approved by the Food and Drug Administration. In a contained casualty setting, parenteral antibiotics are recommended for all symptomatic patients. In a mass casualty incident, local resources must be evaluated, and, if sufficient supplies of parenteral antibiotics are not available, oral antibiotics may be used. Oral antibiotics should also be given for 7 days as postexposure prophylaxis. Individuals refusing postexposure antibiotics should be observed for fever or cough for 1 week, although isolation is not recommended.7,9 Several antibiotics that should not be used for pneumonic plague include rifampin, aztreonam, ceftazidime, cefotetan, and cefazolin.27 Laboratory testing is needed to confirm pneumonic plague. A sputum Gram’s stain should be used emergently because it may reveal bipolar staining gram-negative bacilli or coccobacilli. Y. pestis is described as having a bipolar (also termed safety pin) staining best seen with Giemsa or Wayson stains.28 The only gram-negative bacilli to cause rapidly progressing pulmonary symptoms are Y. pestis and Bacillus anthracis. Blood or sputum cultures should demonstrate growth within 24 to 48 hours, although some laboratory systems may misidentify Y. pestis.29 Laboratory personnel should be notified when Y. pestis is suspected, to decrease the chance of laboratory exposure and to increase the diagnostic yield. Biosafety Level 2 conditions are acceptable for routine laboratory procedures.9 Rapid PCR, if available, can expedite diagnosis.15–17 Serologic tests are useful for bubonic plague, but, because patients do not seroconvert until between 5 and 20 days postexposure, they would be of little use in a pneumonic plague outbreak.5 Because of the severity of pneumonic plague, patients may require advanced supportive measures, including mechanical ventilation, pressors, and invasive monitoring. During the first few hours after initiation of antibiotics, patients must be monitored closely for shock due to bacteriolysis and endotoxin release.11,30 However, continued clinical deterioration despite appropriate antimicrobial treatment should raise the possibility of an antimicrobial-resistant strain of Y. pestis. Multidrug resistant strains have increasingly been reported to occur naturally, as well as via genetic engineering by former Soviet scientists.31 Because of increasing antibiotic resistance, several alternative therapies continue to be investigated, including antibody, phage and bacteriocin therapy, antiinflammatory therapies to mediate the cytokine storm leading to septic shock and death, and compounds that prevent adhesion to the alveolar epithelium or other key cell membranes.11
UNIQUE CONSIDERATIONS Y. pestis must be considered one of the most likely bacteria to be used as a bioterrorism agent. Y. pestis has been used as a biowarfare agent throughout history; it is readily available worldwide in nature and biologic laboratories, and mass production is relatively simple. Although aerosolized Y. pestis is not known to have ever been used, it has been successfully weaponized by the former Soviet Union, and it could be effectively dispersed as an aerosol.9,31 Under proper conditions, such a release could lead to widespread epidemic pneumonic plague with continued human-to-human transmission. Cases would not present for at least 24 hours after exposure. Pneumonic plague is highly contagious and virulent, and antimicrobial treatment must be initiated
707
within 24 hours to improve survival. Without appropriate antibiotic treatment and supportive care, numerous casualties would result.
PITFALLS • Failure to notify appropriate public health and law enforcement agencies when an outbreak of pneumonic plague is suspected or confirmed • Failure to consider pneumonic plague as the etiologic agent in major pneumonia endemics or pandemics • Failure to use droplet precautions and standard precautions in potential cases of pneumonic plague • Failure to initiate specific antibiotic therapy within 24 hours of symptom onset • Failure to provide postexposure antibiotic prophylaxis
REFERENCES 1. APIC Bioterrorism Task Force, CDC Hospital Infections Program Bioterrorism Working Group. Bioterrorism Readiness Plan: A Template for Healthcare Facilities. Available at: http://emergency.cdc.gov/bioterrorism/ pdf/13apr99APIC-CDCBioterrorism.pdf. 2. Butler T. Plague gives surprises in the first decade of the 21st century in the United States and Worldwide. Am J Trop Med Hyg. 2013. Sept;89(4): 788–793. 3. Noah DL, Huebner KD, Darling RG, et al. The history and threat of biological warfare and terrorism. Emerg Med Clin North Am. 2002;20(2): 255–271. 4. Williams P, Wallace D. Unit 731: Japan’s Secret Biological Warfare in World War II. New York: The Free Press; 1989. 5. Dennis DT, Gage KL, Gratz N, et al. Plague Manual: Epidemiology, Distribution, Surveillance and Control. Available at: http://www.who.int/csr/ resources/publications/plague/whocdscsredc992a.pdf. 6. Gani R, Leach S. Epidemiologic determinants for modeling pneumonic plague outbreaks. Emerg Infect Dis. 2004;10(4):608–614. 7. Miller JM. Agents of bioterrorism: preparing for bioterrorism at the community health care level. Infect Dis Clin North Am. 2001;15(4): 1127–1156. 8. US Centers for Disease Control and Prevention. Frequently asked questions (FAQ) about Plague. Available at: http://www.bt.cdc.gov/agent/plague/faq.asp. 9. Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a biological weapon: medical and public health management. JAMA. 2000;283(17): 2281–2290. 10. Mettler FA, Mann JM. Radiographic manifestations of plague in New Mexico, 1975-1980. A review of 42 proved cases. Radiology. 1981;139: 561–565. 11. Anisimov A, Amoako K. Treatment of plague: promising alternatives to antibiotics. J Med Microbiol. 2006;55:1461–1475. 12. Health Aspects of Chemical and Biological Weapons. Geneva, Switzerland: World Health Organization; 1970: 98–109. 13. Cunha BA. Anthrax, tularemia, plague, ebola, or smallpox as agents of bioterrorism: recognition in the emergency room. Clin Microbiol Infect. 2002;8:489–503. 14. Lohmus M, et al. Rodents as potential couriers for bioterrorism agents. Biosecur Bioterr. 2013;1(1):S247–S257. 15. Sun W, Roland K, Curtiss R. Developing live vaccines against Yersinia pestis. J Infect Dev Ctries. 2011;5(9):614–627. 16. Tomaso H, Reisinger E, et al. Rapid detection of Yersinia pestis with multiplex real-time PCR assays using fluorescent hybridisation probes. FEMS Immunol Med Microbiol. 2003. Sept;38(2):117–126. 17. Lindler LE, Fan W, Jahan N. Detection of ciprofloxacin-resistant Yersinia pestis by fluorogenic PCR using the LightCycler. J Clin Microbiol. 2001;39:3649–3655. 18. Loiez C, Herwegh S, et al. Detection of Yersinia pestis in sputum by real-time PCR. J Clin Microbiol. 2003. Oct;41(10):4873–4875.
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19. US Centers for Disease Control and Prevention, the Hospital Infection Control Practices Advisory Committee (HICPAC). Recommendations for isolation precautions in hospitals. Am J Infect Control. 1996;24:24–52. 20. American Public Health Association. Control of Communicable Diseases in Man. Washington, DC: American Public Health Association; 1995. 21. Lowe J, Gibbs S, Iwen P, Smith P, Hewlett A. Decontamination of a hospital room using gaseous chlorine dioxide: Bacillus anthracis, Francisella tularensis, and yersinia pestis. J Occup Environ Hyg. 2013;10(10): 533–539. 22. Meyer K. Pneumonic plague. Bacteriol Rev. 1961;25:249–261. 23. Doll JM, Zeitz PS, Ettestad P, Bucholtz AL, Davis T, Gage K. Cat-transmitted fatal pneumonic plague in a person who traveled from Colorado to Arizona. Am J Trop Med Hyg. 1994;51:109–114. 24. American Hospital Formulary Service. AHFS Drug Information. Bethesda, Md: American Society of Health System Pharmacists; 2000. 25. Scott JL, Finegold SM, Belkin GA, et al. A controlled double blind study of the hematologic toxicity of chloramphenicol. N Engl J Med. 1965;272: 113–142.
26. Watterberg KL, Kelly HW, Angelus P, Backstrom C. The need for a loading dose of gentamicin in neonates. Ther Drug Monit. 1989;11:16–20. 27. Byrne WR, Welkos SL, Pitt ML, et al. Antibiotic treatment of experimental pneumonic plague in mice. Antimicrob Agents Chemother. 1998;42:675–681. 28. McGovern TW, Friedlander AM. Plague. In: Sidell FR, Takafuji ET, Franz DR, eds. Medical Aspects of Chemical and Biological Warfare. Washington, DC: Office of The Surgeon General; 1997:479–502. Available at: https://ke.army.mil/bordeninstitute/published_volumes/ chemBio/Ch23.pdf. 29. Wilmoth BA, Chu MC, Quan TC. Identification of Yersinia pestis by BBL Crystal Enteric/Nonfermenter Identification System. J Clin Microbiol. 1996;34:2829–2830. 30. Jacobs RF, Sowell MK, Moss MM, Fiser DH. Septic shock in children: bacterial etiologies and temporal relationships. Pediatr Infect Dis J. 1990;9:196–200. 31. Alibek K, Handelman S. Biohazard. New York: Random House; 1999.
125
Yersinia pestis (Plague) Attack Kimberly A. Stanford and Jonathan Harris Valente
DESCRIPTION OF EVENT A bioterrorism event leading to multiple cases of the plague would likely result from airborne dispersal of a weaponized form of Yersinia pestis and would cause a pulmonary variant of the plague called pneumonic plague.1 Outbreaks of pneumonic plague have also been reported following natural disasters, such as after the 1994 earthquake in Maharashtra, India, and in war-torn regions, such as the Congo, as recently as the first decade of the twenty-first century.2 During World War II, in two separate incidents, the Japanese dropped clay pots filled with Y. pestis-contaminated rice and fleas over the Chinese cities of Shusien, in Chekiang province, and Changteh, in Hunan province. This tactic led to outbreaks of bubonic plague.3,4 However, it would not be the optimal way for terrorists to spread the plague because bubonic plague requires a bite from a flea. In addition, bubonic plague is not spread directly from person to person as is the pneumonic form. Pneumonic plague may occur as a secondary pneumonia due to hematogenous spread from bubonic plague. This is the most common form of naturally occurring pneumonic plague. Primary pneumonic plague occurs after inhalation of aerosolized Y. pestis bacilli, either from person-to-person transmission or via an intentional attack. Pneumonic plague is rapidly progressive, and it can spread from person to person via aerosolized droplets. The incubation period for pneumonic plague (1 to 6 days) is shorter than that of the bubonic form (2 to 8 days).5,6 Control of the disease would be complex because affected people without knowledge of the exposure could spread disease by travel to other regions.7–9 Pneumonic plague presents clinically as a rapidly progressive respiratory syndrome that is often associated with fever, cough, shortness of breath, chest pain, hemoptysis, malaise, myalgia, nausea and vomiting, sputum or blood cultures with gram-negative rods, and radiographic findings of pneumonia. Chest roentgenograms of patients with pneumonic plague usually show patchy bronchopneumonic infiltrates as well as segmental or lobar consolidation with or without confluence. They may show cavitary lesions or bilateral diffuse infiltrates characteristic of acute respiratory distress syndrome.10 Time from onset of symptoms to fulminant disease is generally less than 24 hours, rapidly progressing to disseminated intravascular coagulation (DIC), circulatory collapse, and respiratory failure.11 It has been estimated that if 50 kg of weaponized Y. pestis were released as an aerosol over a city of 5 million people, pneumonic plague could occur in as many as 150,000 persons, 36,000 of whom would be expected to die.12
PRE-INCIDENT ACTIONS An intentional plague outbreak should be considered one of the most likely bioterrorism scenarios for which emergency providers need to
prepare. Pneumonic plague would most likely occur naturally as a complication of bubonic plague in the setting of a major bubonic plague outbreak.13 Warning the public to avoid contact with dead animals, especially rodents such as marmots, is an important preventive measure following a natural disaster such as a large earthquake.14 Y. pestis is not stable in the environment, and it is readily destroyed by drying and sunlight exposure. If Y. pestis were released into the air in a bioterrorism attack, it would likely survive for less than an hour. Because of these factors, preparation for environmental decontamination is less important than it would be in other similar attacks, such as with anthrax.8,9,12 No vaccine is currently available. The U.S. manufactured vaccine, a killed whole-cell vaccine (Greer), was discontinued in 1999 because of significant adverse effects and because it was not protective for the pneumonic form of the plague. Subunit vaccines based on rF1V and LcrV antigens are currently undergoing clinical trials, and these are the most promising prospects, but efficacy against pneumonic plague, specifically, is unclear. Live attenuated vaccine is likely the best option in this regard, but it carries the risk of reversion to virulence, limiting its utility.15 There are no early-warning systems for the detection of Y. pestis if an aerosolized form were dispersed. A real-time PCR has been developed with the potential for identification of Y. pestis in less than 5 hours, from blood or sputum, including identification of specific strains such as ciprofloxacin-resistant.16–18 However, newly engineered strains for use as bioterrorist agents might not be detected by this assay, and thus culture and biochemical identification must still be used for confirmation.
POST-INCIDENT ACTIONS All cases of pneumonic plague should be considered terrorism-related until proven otherwise. Hospital infection control officers and local and state, national health, and law enforcement officials should be notified immediately of any suspected cases of the plague. The risk for reaerosolization of Y. pestis from the contaminated clothing of exposed persons is low. Under ideal conditions, Y. pestis can survive in the environment for about 1 hour, and since patients will present with symptoms after 24 hours, there is no need for routine decontamination. In situations where there may have been recent, gross exposure to Y. pestis, decontamination of skin and potentially contaminated fomites (e.g., clothing or environmental surfaces) may be considered to reduce the risk of cutaneous or bubonic forms of the disease. The plan for decontaminating patients may include several steps. Patients should be instructed to remove contaminated clothing. Clothing should be stored in labeled, plastic bags and gently handled to avoid dispersal of Y. pestis. Patients should be instructed to shower thoroughly with soap and water. Environmental surface decontamination may be performed using an Environmental
705
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SECTION XII
Biological Events, Part 1: Bacterial Agents
Protection Agency-registered, facility-approved sporicidal/germicidal agent or a 0.5% hypochlorite solution (one part household bleach added to nine parts water).1,19,20 In addition to standard decontamination procedures, chlorine dioxide gas has been shown to rapidly deactivate almost 100% of Y. pestis in a hospital environment, but further studies are needed regarding safe usage.21 In its natural form, pneumonic plague is transmitted person to person via large droplets (not via fine-particle aerosol), and it requires close personal contact (2 m or less) for effective transmission.5,22,23 Patients with symptoms suggestive of pneumonic plague should be isolated using droplet precautions in addition to standard precautions. Patients with suspected pneumonic plague should be placed in a private room when possible. It is appropriate to cohort symptomatic patients with similar symptoms and the same presumptive diagnosis (i.e., pneumonic plague) when private rooms are not available. Maintain spatial separation of at least 3 feet between infected patients and others when
TABLE 125-1
Recommendations for Antimicrobial Treatment of Pneumonic Plague* PATIENT CATEGORY
Loading dose followed
MEDICAL TREATMENT OF CASUALTIES Specific antibiotic treatment must be initiated within 24 hours after symptom onset, otherwise pneumonic plague is nearly uniformly
TABLE 125-1
Recommendations for Antimicrobial Treatment of Pneumonic Plague—cont'd PATIENT CATEGORY
RECOMMENDED THERAPY
Childrenk
Preferred choice Doxycycline†† If <45 kg, 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},** Preferred choices Doxycycline, 100 mg orally twice daily†† Ciprofloxacin, 500 mg orally twice daily Alternative choices Chloramphenicol, 25 mg/kg orally 4 times daily},**
RECOMMENDED THERAPY
Contained Casualty Setting Adults Preferred choices Streptomycin, 1 g 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 3 times daily† Alternative choices (first choice for postexposure prophylaxis) 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} k 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/d) Ciprofloxacin, 15 mg/kg IV twice daily{ Chloramphenicol, 25 mg/kg IV 4 times daily} Pregnant women}
cohorting is not possible. Avoid placement of patients requiring droplet precautions in the same room with an immunocompromised patient. Special air handling is not necessary, and doors may remain open. Patient transport should be limited to essential medical purposes. When transport is necessary, minimize dispersal of droplets by placing a surgical-type mask on the patient. Isolation precautions should be continued for 2 days after initiation of antibiotics and until some clinical improvement occurs in patients with pneumonic plague.9
Preferred choice Gentamicin, 5 mg/kg IM or IV once daily or 2 mg/kg By 1.7 mg/kg IM or IV 3 times daily† Alternative choices Doxycycline, 100 mg IV twice daily or 200 mg IV once daily Ciprofloxacin, 400 mg IV twice daily{
Mass Casualty Setting and Postexposure Prophylaxis# Adults Preferred choices Doxycycline, 100 mg orally twice daily†† Ciprofloxacin, 500 mg orally twice daily{ Alternative choice Chloramphenicol, 25 mg/kg orally 4 times daily},**
Pregnant women}
*These are consensus recommendations of the Working Group on Civilian Biodefense and are not necessarily approved by the Food and Drug Administration. One antimicrobial agent should be selected. Therapy should be continued for 10 days. Oral therapy should be substituted when patient’s condition improves. IM indicates intramuscularly; IV, intravenously. † Aminoglycosides must be adjusted according to renal function. Evidence suggests that gentamicin, 5 mg/kg IM or IV once daily, would be efficacious in children, although this is not yet widely accepted in clinical practice. Neonates up to 1 week of age and premature infants should receive gentamicin, 2.5 mg/kg IV twice daily. { 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 μg/mL can cause reversible bone marrow suppression.24,25 k Refer to “Management of Special Groups” for details. In children, ciprofloxacin dose should not exceed 1 g/d, chloramphenicol should not exceed 4 g/d. Children younger than 2 years should not receive chloramphenicol. } In neonates, gentamicin loading dose of 4 mg/kg should be given initially.26 # Duration of treatment of plague in mass casualty setting is 10 days. Duration of postexposure prophylaxis to prevent plague infection is 7 days. **Children younger than 2 years should not receive chloramphenicol. Oral formulation available only outside the United States. †† Tetracycline could be substituted for doxycycline. (From Inglesby TV, et al. Consensus Statement: Plague as a Biological Weapon: Medical & Public Health Management. JAMA. 2000;283[17]: 2281-90.)
CHAPTER 125 Yersinia pestis (Plague) Attack fatal.7,9 Table 125-1 shows the Working Group on Civilian Biodefense’s antibiotic recommendations for pneumonic plague.9 These consensusbased recommendations cover contained exposures, mass casualty exposures, and postexposure prophylaxis. They are based on the best available evidence. However, it should be noted that there is a lack of published trials in treating plague in humans, and a limited number of studies in animals. A number of possible therapeutic regimens for treating plague have not been prospectively studied or approved by the Food and Drug Administration. In a contained casualty setting, parenteral antibiotics are recommended for all symptomatic patients. In a mass casualty incident, local resources must be evaluated, and, if sufficient supplies of parenteral antibiotics are not available, oral antibiotics may be used. Oral antibiotics should also be given for 7 days as postexposure prophylaxis. Individuals refusing postexposure antibiotics should be observed for fever or cough for 1 week, although isolation is not recommended.7,9 Several antibiotics that should not be used for pneumonic plague include rifampin, aztreonam, ceftazidime, cefotetan, and cefazolin.27 Laboratory testing is needed to confirm pneumonic plague. A sputum Gram’s stain should be used emergently because it may reveal bipolar staining gram-negative bacilli or coccobacilli. Y. pestis is described as having a bipolar (also termed safety pin) staining best seen with Giemsa or Wayson stains.28 The only gram-negative bacilli to cause rapidly progressing pulmonary symptoms are Y. pestis and Bacillus anthracis. Blood or sputum cultures should demonstrate growth within 24 to 48 hours, although some laboratory systems may misidentify Y. pestis.29 Laboratory personnel should be notified when Y. pestis is suspected, to decrease the chance of laboratory exposure and to increase the diagnostic yield. Biosafety Level 2 conditions are acceptable for routine laboratory procedures.9 Rapid PCR, if available, can expedite diagnosis.15–17 Serologic tests are useful for bubonic plague, but, because patients do not seroconvert until between 5 and 20 days postexposure, they would be of little use in a pneumonic plague outbreak.5 Because of the severity of pneumonic plague, patients may require advanced supportive measures, including mechanical ventilation, pressors, and invasive monitoring. During the first few hours after initiation of antibiotics, patients must be monitored closely for shock due to bacteriolysis and endotoxin release.11,30 However, continued clinical deterioration despite appropriate antimicrobial treatment should raise the possibility of an antimicrobial-resistant strain of Y. pestis. Multidrug resistant strains have increasingly been reported to occur naturally, as well as via genetic engineering by former Soviet scientists.31 Because of increasing antibiotic resistance, several alternative therapies continue to be investigated, including antibody, phage and bacteriocin therapy, antiinflammatory therapies to mediate the cytokine storm leading to septic shock and death, and compounds that prevent adhesion to the alveolar epithelium or other key cell membranes.11
UNIQUE CONSIDERATIONS Y. pestis must be considered one of the most likely bacteria to be used as a bioterrorism agent. Y. pestis has been used as a biowarfare agent throughout history; it is readily available worldwide in nature and biologic laboratories, and mass production is relatively simple. Although aerosolized Y. pestis is not known to have ever been used, it has been successfully weaponized by the former Soviet Union, and it could be effectively dispersed as an aerosol.9,31 Under proper conditions, such a release could lead to widespread epidemic pneumonic plague with continued human-to-human transmission. Cases would not present for at least 24 hours after exposure. Pneumonic plague is highly contagious and virulent, and antimicrobial treatment must be initiated
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within 24 hours to improve survival. Without appropriate antibiotic treatment and supportive care, numerous casualties would result.
PITFALLS • Failure to notify appropriate public health and law enforcement agencies when an outbreak of pneumonic plague is suspected or confirmed • Failure to consider pneumonic plague as the etiologic agent in major pneumonia endemics or pandemics • Failure to use droplet precautions and standard precautions in potential cases of pneumonic plague • Failure to initiate specific antibiotic therapy within 24 hours of symptom onset • Failure to provide postexposure antibiotic prophylaxis
REFERENCES 1. APIC Bioterrorism Task Force, CDC Hospital Infections Program Bioterrorism Working Group. Bioterrorism Readiness Plan: A Template for Healthcare Facilities. Available at: http://emergency.cdc.gov/bioterrorism/ pdf/13apr99APIC-CDCBioterrorism.pdf. 2. Butler T. Plague gives surprises in the first decade of the 21st century in the United States and Worldwide. Am J Trop Med Hyg. 2013. Sept;89(4): 788–793. 3. Noah DL, Huebner KD, Darling RG, et al. The history and threat of biological warfare and terrorism. Emerg Med Clin North Am. 2002;20(2): 255–271. 4. Williams P, Wallace D. Unit 731: Japan’s Secret Biological Warfare in World War II. New York: The Free Press; 1989. 5. Dennis DT, Gage KL, Gratz N, et al. Plague Manual: Epidemiology, Distribution, Surveillance and Control. Available at: http://www.who.int/csr/ resources/publications/plague/whocdscsredc992a.pdf. 6. Gani R, Leach S. Epidemiologic determinants for modeling pneumonic plague outbreaks. Emerg Infect Dis. 2004;10(4):608–614. 7. Miller JM. Agents of bioterrorism: preparing for bioterrorism at the community health care level. Infect Dis Clin North Am. 2001;15(4): 1127–1156. 8. US Centers for Disease Control and Prevention. Frequently asked questions (FAQ) about Plague. Available at: http://www.bt.cdc.gov/agent/plague/faq.asp. 9. Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a biological weapon: medical and public health management. JAMA. 2000;283(17): 2281–2290. 10. Mettler FA, Mann JM. Radiographic manifestations of plague in New Mexico, 1975-1980. A review of 42 proved cases. Radiology. 1981;139: 561–565. 11. Anisimov A, Amoako K. Treatment of plague: promising alternatives to antibiotics. J Med Microbiol. 2006;55:1461–1475. 12. Health Aspects of Chemical and Biological Weapons. Geneva, Switzerland: World Health Organization; 1970: 98–109. 13. Cunha BA. Anthrax, tularemia, plague, ebola, or smallpox as agents of bioterrorism: recognition in the emergency room. Clin Microbiol Infect. 2002;8:489–503. 14. Lohmus M, et al. Rodents as potential couriers for bioterrorism agents. Biosecur Bioterr. 2013;1(1):S247–S257. 15. Sun W, Roland K, Curtiss R. Developing live vaccines against Yersinia pestis. J Infect Dev Ctries. 2011;5(9):614–627. 16. Tomaso H, Reisinger E, et al. Rapid detection of Yersinia pestis with multiplex real-time PCR assays using fluorescent hybridisation probes. FEMS Immunol Med Microbiol. 2003. Sept;38(2):117–126. 17. Lindler LE, Fan W, Jahan N. Detection of ciprofloxacin-resistant Yersinia pestis by fluorogenic PCR using the LightCycler. J Clin Microbiol. 2001;39:3649–3655. 18. Loiez C, Herwegh S, et al. Detection of Yersinia pestis in sputum by real-time PCR. J Clin Microbiol. 2003. Oct;41(10):4873–4875.
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Biological Events, Part 1: Bacterial Agents
19. US Centers for Disease Control and Prevention, the Hospital Infection Control Practices Advisory Committee (HICPAC). Recommendations for isolation precautions in hospitals. Am J Infect Control. 1996;24:24–52. 20. American Public Health Association. Control of Communicable Diseases in Man. Washington, DC: American Public Health Association; 1995. 21. Lowe J, Gibbs S, Iwen P, Smith P, Hewlett A. Decontamination of a hospital room using gaseous chlorine dioxide: Bacillus anthracis, Francisella tularensis, and yersinia pestis. J Occup Environ Hyg. 2013;10(10): 533–539. 22. Meyer K. Pneumonic plague. Bacteriol Rev. 1961;25:249–261. 23. Doll JM, Zeitz PS, Ettestad P, Bucholtz AL, Davis T, Gage K. Cat-transmitted fatal pneumonic plague in a person who traveled from Colorado to Arizona. Am J Trop Med Hyg. 1994;51:109–114. 24. American Hospital Formulary Service. AHFS Drug Information. Bethesda, Md: American Society of Health System Pharmacists; 2000. 25. Scott JL, Finegold SM, Belkin GA, et al. A controlled double blind study of the hematologic toxicity of chloramphenicol. N Engl J Med. 1965;272: 113–142.
26. Watterberg KL, Kelly HW, Angelus P, Backstrom C. The need for a loading dose of gentamicin in neonates. Ther Drug Monit. 1989;11:16–20. 27. Byrne WR, Welkos SL, Pitt ML, et al. Antibiotic treatment of experimental pneumonic plague in mice. Antimicrob Agents Chemother. 1998;42:675–681. 28. McGovern TW, Friedlander AM. Plague. In: Sidell FR, Takafuji ET, Franz DR, eds. Medical Aspects of Chemical and Biological Warfare. Washington, DC: Office of The Surgeon General; 1997:479–502. Available at: https://ke.army.mil/bordeninstitute/published_volumes/ chemBio/Ch23.pdf. 29. Wilmoth BA, Chu MC, Quan TC. Identification of Yersinia pestis by BBL Crystal Enteric/Nonfermenter Identification System. J Clin Microbiol. 1996;34:2829–2830. 30. Jacobs RF, Sowell MK, Moss MM, Fiser DH. Septic shock in children: bacterial etiologies and temporal relationships. Pediatr Infect Dis J. 1990;9:196–200. 31. Alibek K, Handelman S. Biohazard. New York: Random House; 1999.