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Biosecurity Briefing
Mouse Study Evaluates 2 Pneumonic Plague Drugs By Crystal Franco, August 3, 2007 On July 19, 2007, the Journal of Infectious Diseases (JID) published a study comparing the use of two antibiotics (doxycycline and gentamicin) for treatment of mice infected with an aerosol of the plague bacteria Yersinia pestis. Y. pestis causes the deadly pneumonic plague, which has a nearly 100% mortality rate if left untreated. Y. pestis is considered by public health and homeland security officials to be a likely target for use in “incidents of bioterrorism and biowarfare.” Based on this threat, the authors of the study believe there is a “critical need for evaluating new drugs and dosing schedules for the treatment of Y. pestis infection.”1 Until recently, streptomycin has been “the standard antibiotic [treatment]” for pneumonic plague. However, streptomycin can cause hearing damage, must be given through injection, and is not widely available. The JID study evaluates doxycycline and gentamicin as “potential replacements for streptomycin.”1 In order to evaluate the effectiveness of the two antibiotics, scientists first exposed mice to lethal doses of aerosolized Y. pestis. Two types of mice were used: normal mice, and neutropenic mice—i.e. mice with a low white blood cell count, and thus a poor immune response. Control mice were treated with saline (negative control) or levofloxacin—an antibiotic that has shown promise as a treatment for plague—at 15mg/kg every 12 hours (positive control). Test mice were treated either with doxycycline at 40mg/kg every 6 hours or 48mg/kg of gentamicin administered via three different dosing schedules: 12 mg/kg every 6 hours, 24 mg/kg every 12 hours, or 48 mg/kg every 48 hours.1 Following completion of the antibiotic treatment schedule scientists found that normal mice treated with doxycycline survived 90% of the time, while all neutropenic mice treated with doxycycline died “after treatment was terminated.” In contrast, both normal and neutropenic mice treated with gentamicin had a 70%-100% survival rate after treatment ended. The authors determined that the dosing schedule for gentamicin made no significant difference in the survival of the mice. Additionally, all negative control mice died, while 100% of the positive controls treated with levofloxacin survived. According to the study, both doxycycline and gentamicin act by inhibiting bacterial protein synthesis. However, gentamicin actually kills the Y. pestis bacteria while doxycycline inhibits bacteria growth and reproduction but does not kill the cells. The authors conclude that because doxycycline does not kill the plague bacteria, “the immune system must play a far more important role in the ultimate therapeutic success of [the drug].” Doxycycline “requires an intact immune system for clearance of the infection after aerosol challenge with Y. pestis.”1 Derived from the study findings, the authors recommend that decisions prioritizing the use of these drugs in an outbreak of pneumonic plague be based on three considerations:
Doxycycline is the least toxic of the candidate antibiotics, can be given orally, and is inexpensive. According to the authors, doxycycline should be the first choice for mass post-exposure prophylaxis. However, gentamicin is likely a better choice for those patients in later stages of infection or for immunocompromised individuals. Finally, levofloxacin, while more expensive than gentamicin, appears to be a highly effective treatment and should be considered as a third alternative.1 References
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