Plague

Treatment Overview

Antibiotics. Prompt initiation of appropriate antibiotics is paramount for reducing mortality; this is especially true in primary pneumonic plague, for which mortality approaches 100% if adequate therapy is not initiated within 18-24 hours of onset of symptoms. Initial empiric therapy for systemic disease caused by Y. pestis includes at least one of the following antibiotics:

Preferred

  • Streptomycin(FDA Approved)*, 1g IM bid (15 mg/kg IM bid for children (up to 2g/day)), or
  • Gentamicin 5 mg/kg IM or IV qd, or 2mg/kg loading dose followed by 1.7mg/kg IM or IV q 8 hr (2.5mg/kg IV q 8 hr for children),(adjusted for renal clearance), or

Alternatives

  • Doxycycline(FDA Approved), 100 mg IV q12 hr or 200mg IV qd for adults or children >= 45kg (2.2 mg/kg IV q 12 hr for children <45 kg), or
  • Ciprofloxacin 400 mg IV every 12 hr for adults (for children use 15 mg/g IV q 12 hr (up to 1g/day)), or
  • Chloramphenicol, 25 mg/kg IV, then 15mg/kg IV q 6 hr (adjusted for serum levels, and not for children less than 2 years of age)

Intravenous antibiotics can be switched to oral antibiotics as the improvement in the patient's clinical course dictates, to complete at least 10-14 total days of therapy. For treatment of plague meningitis add intravenous chloramphenicol. Patients with uncomplicated bubonic plague often demonstrate resolution of fever and other systemic symptoms within 3-5 days, while more complicated bubonic disease, septicemic, and pneumonic plague often result in extended hospital courses.

It is imperative that antibiotics are adjusted for demonstrated susceptibility patterns for the infecting strain; naturally-occurring strains have been reported which are resistant to streptomycin, tetracyclines, and chloramphenocol, and it is anticipated that weaponized plague could be intentionally rendered antibiotic resistant. Despite typically good in vitro susceptibilities to penicillins and cephalosporins, these antibiotics are generally felt to be ineffective in treating plague; in fact, animal studies suggest that beta-lactam antibiotics may accelerate mortality in bacteremic mice. Macrolide antibiotics are ineffective for plague.

*Streptomycin has historically been the drug of choice for plague and is the only aminoglycoside antibiotic approved by the FDA for treatment of plague; however, since it may not be readily available immediately after a large-scale BW attack, gentamicin and other alternative drugs should be considered first. Requests for streptomycin should be directed to the Roerig Streptomycin Program at Pfizer Pharmaceuticals in New York (800-254-4445).

Supportive therapy includes intravenous crystalloids and hemodynamic monitoring. Although low-grade disseminated intravascular coagulation may occur, clinically significant hemorrhage is uncommon, as is the need to treat with heparin. Endotoxic shock is common, but pressor agents are rarely needed. Finally, buboes rarely require any form of local care, but instead recede with systemic antibiotic therapy. In fact, incision and drainage poses a risk to others in contact with the patient due to aerosolization of the bubo contents. Needle aspiration is recommended for diagnostic purposes and may provide symptomatic relief.

Infection Control. Use Standard precautions for bubonic and septicemic plague patients. Suspected pneumonic plague cases require strict isolation with respiratory droplet precautions for at least 48 hours of antibiotic therapy, or until sputum cultures are negative in confirmed cases. Historically, epidemics of pneumonic plague have subsided rapidly with implementation of such relatively simple infection control measures. Pneumonic plague patients being transported should wear a surgical mask when feasible. If competent vectors (fleas) and reservoirs (rodents) are present, measures must be taken to prevent local disease cycles. These might include, but are not limited to, use of flea insecticides, rodent control measures (after or during flea control), and flea barriers for patient care areas.

Treatment

General Considerations

Safe and effective medical countermeasures (MCMs) (drugs, vaccines, diagnostics, and other products) are needed for plague and other threats. A recent report described the status of MCM development, acquisition, stockpiling, and distribution in the United States (see References: National Biodefense Science Board 2010). A summary of the status of MCMs for plague is as follows:

  • Diagnostics: MCMs are neither licensed by the US Food and Drug Administration (FDA) nor stocked by the Strategic National Stockpile (SNS); however, they are national priorities and are being pursued. Specifically, the US Department of Defense has developed an integrated system for rapid identification and diagnostic confirmation of biological agent exposure or infection (the Joint Biological Agent Identification and Diagnostic System).
  • Vaccines: Candidate MCMs are not yet licensed by the FDA.
  • Antibiotics: MCMs are licensed or approved by the FDA and are stocked by the SNS; additionally, products that have been licensed or approved for other uses are eligible for use as MCMs under emergency use authorization.

Treatment

Traditionally, streptomycin, tetracycline, and doxycycline have been used for the treatment of plague and are approved by the FDA for this indication. Gentamicin also has been shown to be efficacious for plague treatment, although it is not currently approved by the FDA (see References: Boulanger 2004, Crook 1992, Welty 1985). In the United States, supplies of streptomycin are limited, and it is rarely used for plague treatment (see References: Worsham 2007).

Doxycycline and gentamicin regimens have been compared in mice receiving aerosolized Y pestis. Survival was similar with both drugs, although because doxycylcine behaved in vivo as a bacteriostatic drug, it required an intact immune system for clearance of infection after challenge (see References: Heine 2007).

Clinical experience with the fluoroquinolones in treating plague is limited; however, animal studies have suggested efficacy in this setting (see References: Russell 1996). An in vitro pharmacodynamic infection model showed that a regimen of levofloxacin was superior to a regimen of streptomycin (see References: Louie 2007). Streptomycin therapy caused a reduction in the number of bacteria over 24 hours, followed by regrowth with streptomycin-resistant mutants. Levofloxacin resulted in a greater reduction in the number of bacteria within 12 hours and ultimately sterilized the culture without resistance selection.

A randomized, comparative, open-label clinical trial involving monotherapy with gentamicin or doxycycline found that both antibiotics were effective in treatment of plague (see References: Mwengee 2006). The patients studied had bubonic, septicemic, or pneumonic plague; 35 patients were randomized to receive gentamicin and 30 to receive doxycycline. Three patients died (two were treated with gentamicin and one with doxycycline); all had advanced disease or complications at the start of therapy. The overall effectiveness of treatment was 94% for gentamicin and 97% for doxycycline.

Rifampin, aztreonam, ceftazidime, cefotetan, and cefazolin have been shown to not be efficacious and should not be used to treat plague.

Some investigators have suggested alternative therapies for treatment of plague, such as immunotherapy, non-pathogen-specific immunomodulatory therapy, bacteriocin therapy, treatment with inhibitors of virulence factors, and phage therapy (see References: Anisimov 2006).

Potential adverse effects to the fetus are governed by the time of antibiotic therapy; however, during outbreaks and bioterrorism emergencies, treatment benefits for the mother outweigh fetal risk (see References: Cono 2006). Antibiotics should be administered to infants born to infected mothers (see References: Welty 1985).

Breast-feeding women and their infants should be treated with the same antibiotic. The medication that is safest for the infant generally should be considered the first choice (ie, gentamicin in the contained casualty setting and doxycycline in the mass- casualty setting). Fluoroquinolone antibiotics would be the recommended alternative in both settings (see References: Inglesby 2000).

Treatment for bubonic plague

The initial cases in a bioterrorist attack would be expected to be pneumonic plague from exposure to the initial aerosol release and the occurrence of secondary cases with respiratory droplet transmission. It is also conceivable that, as the epidemic progressed, some cases of bubonic plague might occur from contact with infected animals in the area (ie, bites, scratches) or even from subsequent flea bites (see References: McGovern 1999).

Antibiotic treatment of bubonic plague is the same as therapy for pneumonic plague (see below). Usually buboes will recede without intervention, but if they become fluctuant or secondarily infected, they made need incision and drainage.

Treatment for pneumonic plague

The Working Group on Civilian Biodefense has developed consensus-based recommendations for treatment of pneumonic plague during a bioterrorist attack (see References: Inglesby 2000). The working group made the following recommendations:

  • In a contained casualty setting where the medical care delivery system can effectively manage the number of patients, parenteral antibiotics should be administered to all patients whenever possible, according to the table below.
  • In a mass-casualty setting where the medical care delivery system is not able to meet the demands for patient care, use of oral antibiotics may be necessary. In such a situation, the medications listed below in the table on antibiotic postexposure prophylaxis should be used, except that treatment should be given for 10 days instead of 7 days.
  • Supportive care of patients also is critical, including fluid management and hemodynamic monitoring. Many patients would require intensive care with respiratory support owing to complications of gram-negative sepsis (eg, shock, adult respiratory distress syndrome, multisystem failure, DIC).
  • Bioterrorist use of a Y pestis strain resistant to conventional antibiotic therapy is of concern and should be considered, particularly if patients deteriorate despite early initiation of antibiotic therapy. Clinical isolates of Y pestis with plasmid-mediated drug resistance have been identified in Madagascar (see References: Galimand 1997, Galimand 2006).

Recommendations From the Working Group on Civilian Biodefense for Treatment of Pneumonic Plague During a Bioterrorism Event

Choices by Patient Category

Therapy Recommendationsa

Adults: Preferred choices

Streptomycin: 1 g IM twice daily for 10 daysb
or
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 for 10 daysc,d

Adults: Alternative choicese

Doxycycline: 100 mg IV twice daily or 200 mg IV once daily for 10 daysd
or
Ciprofloxacin: 400 mg IV twice daily for 10 daysd,f
or
Chloramphenicol: 25 mg/kg IV 4 times daily for 10 daysg

Children: Preferred choices

Streptomycin: 15 mg/kg IM twice daily (maximum daily dose, 2 g)
or
Gentamicin: 2.5 mg/kg IM or IV 3 times daily for 10 daysc

Children: Alternative choicese

Doxycycline:
    >45 kg: same as adult
   <45 kg: 2.2 mg/kg IV twice daily for 10 days (maximum, 200 mg/day)
or
Ciprofloxacin, 15 mg/kg IV twice daily for 10 days (maximum daily dose, 1 g)f
or
Chloramphenicol: 25 mg/kg IV 4 times daily for 10 days (maximum daily dose, 4 g)g,h

Abbreviations: IM, intramuscularly; IV, intravenously.

aThese recommendations are most appropriate for the contained casualty setting where resources are adequate to treat all patients with IV antibiotics. In the mass-casualty setting where the medical care delivery system is not able to meet the demands for patient care, oral antibiotics may need to be substituted for IV antibiotics for treatment of patients with plague. In such a situation, the recommendations in the table on postexposure prophylaxis should be followed for treatment, except that treatment should be continued for 10 days instead of 7 days.
bStreptomycin is not acceptable for use in pregnant women because irreversible deafness in children exposed in utero has been reported.
cAminoglycosides must be adjusted according to renal function.
dAcceptable for pregnant women. Although fetal toxicity may occur with doxycycline use, the Working Group on Civilian Biodefense recommended doxycycline or ciprofloxacin if gentamicin is not available or if oral antibiotics must be used.
eTrimethoprim-sulfamethoxazole has been used successfully to treat plague; however, the working group considers this agent as a second-tier choice.
fOther fluoroquinolones may be substituted at dosages appropriate for age.
gConcentration should be maintained between 5 and 20 mcg/mL; concentrations >25 mcg/mL can cause reversible bone marrow suppression. The oral formulation is available only outside the United States. Some experts have recommended that chloramphenicol be used to treat patients with plague meningitis, since chloramphenicol penetrates the blood-brain barrier (see References: AAP 2006, Butler 1991, Dennis 1997); however, controlled trials to verify improvement in outcome have not been performed.
hAccording to the working group, children younger than 2 years of age should not receive chloramphenicol. However, the American Academy of Pediatrics (AAP) has recommended chloramphenicol as the drug of choice for treating plague meningitis in children. The AAP Red Book does not indicate that chloramphenicol should not be given to children with serious infections who are beyond the newborn period but younger than 2 years of age (see References: AAP 2006).

Adapted from Inglesby 2000 (see References).

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