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Antimicrob Agents Chemother. Evaluation of Imipenem for the Prophylaxis and Therapy of Yersinia pestis Delivered by Aerosol in a Mouse Model of Pneumonic Plague
[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
Evaluation of Imipenem for the Prophylaxis and Therapy of Yersinia pestis Delivered by Aerosol in a Mouse Model of Pneumonic Plague
Henry S. Heine 1, Arnold Louie 1, Jeffrey J. Adamovicz 2, Kei Amemiya 3, Randy L. Fast 3, Lynda Miller 3, Steven M. Opal 4, John Palardy 4, Nicolas A. Parejo 4, Fritz S?rgel 5,6, Martina Kinzig-Schippers 5 and George L. Drusano 1
Author Affiliations: <SUP>1</SUP>Institute for Innovative Therapeutics, University of Florida, UFRAC Orlando, Fl - <SUP>2</SUP>University of Wyoming, Laramie,Wyoming - <SUP>3</SUP>US Army Medical Research Institute of Infectious Diseases, Ft. Detrick, Maryland - <SUP>4</SUP>Alpert Medical School of Brown University, Providence, RI - <SUP>5</SUP>Inst. Biomedical and Pharmaceutical Research, Nurnberg-Heroldsburg, Germany - <SUP>6</SUP>Inst. of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Germany.
ABSTRACT
It has been previously shown that mice subjected to an aerosol exposure of Yersinia pestis and treated with β-lactam antibiotics after a delay of 42h died at an accelerated rate compared to controls. It was hypothesized that endotoxin release in antibiotic treated mice accounted for the accelerated death rate in the plague aerosolized mice. Imipenem, a β-lactam antibiotic, binds to penicillin binding protein-2 with the highest affinity and produces rounded cells. The binding of imipenem causes cells to lyse quickly and thereby release less free endotoxin. Two imipenem regimens producing ?fractional free drug, time above MIC? (fT>MIC) of approximately 25% (6/24h) or 40% (9.5/24h) were evaluated. In the post-exposure prophylaxis study, the 40% and 25% regimens produced a 90% and 40% survivorship. In the 42h treatment study both regimens demonstrated a 40-50% survivorship at therapy cessation, and some deaths thereafter, resulting in a 30% survivorship. As this was an improvement over other β-lactams a comparison of both endotoxin and cytokine levels in mice treated with imipenem and ceftazidime (a β-lactam previously demonstrated to accelerate death in mice during treatment) support the original hypotheses; however, the levels observed from ciprofloxacin treated animals (included as an unrelated antibiotic that is also bactericidal but should cause little lysis due to a different mode of action) were elevated and significantly (7 fold) higher than ceftazidime.
FOOTNOTES
Corresponding Author: Henry S. Heine, Ph.D., Program Director, Institute for Innovative Therapeutics, University of Florida, UFRAC at Lake Nona, 6550 Sanger Rd., Orlando, FL 32827, Email: hsheine@ufl.edu, Telephone: (407)313-7062, FAX: (407)313-7096
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
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Evaluation of Imipenem for the Prophylaxis and Therapy of Yersinia pestis Delivered by Aerosol in a Mouse Model of Pneumonic Plague
Henry S. Heine 1, Arnold Louie 1, Jeffrey J. Adamovicz 2, Kei Amemiya 3, Randy L. Fast 3, Lynda Miller 3, Steven M. Opal 4, John Palardy 4, Nicolas A. Parejo 4, Fritz S?rgel 5,6, Martina Kinzig-Schippers 5 and George L. Drusano 1
Author Affiliations: <SUP>1</SUP>Institute for Innovative Therapeutics, University of Florida, UFRAC Orlando, Fl - <SUP>2</SUP>University of Wyoming, Laramie,Wyoming - <SUP>3</SUP>US Army Medical Research Institute of Infectious Diseases, Ft. Detrick, Maryland - <SUP>4</SUP>Alpert Medical School of Brown University, Providence, RI - <SUP>5</SUP>Inst. Biomedical and Pharmaceutical Research, Nurnberg-Heroldsburg, Germany - <SUP>6</SUP>Inst. of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Germany.
ABSTRACT
It has been previously shown that mice subjected to an aerosol exposure of Yersinia pestis and treated with β-lactam antibiotics after a delay of 42h died at an accelerated rate compared to controls. It was hypothesized that endotoxin release in antibiotic treated mice accounted for the accelerated death rate in the plague aerosolized mice. Imipenem, a β-lactam antibiotic, binds to penicillin binding protein-2 with the highest affinity and produces rounded cells. The binding of imipenem causes cells to lyse quickly and thereby release less free endotoxin. Two imipenem regimens producing ?fractional free drug, time above MIC? (fT>MIC) of approximately 25% (6/24h) or 40% (9.5/24h) were evaluated. In the post-exposure prophylaxis study, the 40% and 25% regimens produced a 90% and 40% survivorship. In the 42h treatment study both regimens demonstrated a 40-50% survivorship at therapy cessation, and some deaths thereafter, resulting in a 30% survivorship. As this was an improvement over other β-lactams a comparison of both endotoxin and cytokine levels in mice treated with imipenem and ceftazidime (a β-lactam previously demonstrated to accelerate death in mice during treatment) support the original hypotheses; however, the levels observed from ciprofloxacin treated animals (included as an unrelated antibiotic that is also bactericidal but should cause little lysis due to a different mode of action) were elevated and significantly (7 fold) higher than ceftazidime.
FOOTNOTES
Corresponding Author: Henry S. Heine, Ph.D., Program Director, Institute for Innovative Therapeutics, University of Florida, UFRAC at Lake Nona, 6550 Sanger Rd., Orlando, FL 32827, Email: hsheine@ufl.edu, Telephone: (407)313-7062, FAX: (407)313-7096
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
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