Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
Hollow Fiber Pharmacodynamic Studies and Mathematical Modeling to Predict the Efficacy of Amoxicillin for Anthrax Postexposure Prophylaxis in Pregnant Women and Children
Arnold Louie, M.D.*, Brian VanScoy, B.S., Weiguo Liu, M.D., Robert Kulawy, B.S. and G.L. Drusano, M.D.
Author Affiliations: Institute for Therapeutic Innovation, University of Florida College of Medicine, 6550 Sanger Road, Orlando, FL, 32827
ABSTRACT
Background:
Amoxicillin is considered an option for postexposure prophylaxis of Bacillus anthracis (BA) in pregnant and postpartum women who are breastfeeding and in children because of the potential toxicities of ciprofloxacin and doxycycline to the fetus and child. The amoxicillin regimen that effectively kills BA and prevents resistance is unknown.
Methods:
Fourteen-day dose-range and dose-fractionation studies were conducted in in vitro pharmacodynamic models to identify the exposure intensity and pharmacodynamic index of amoxicillin that are linked with optimized killing of BA and resistance prevention. Studies with dicloxacillin, a drug resistant to BA β-lactamase, evaluated the role of β-lactamase production on the pharmacodynamic indices for BA killing and resistance prevention.
Results:
Dose-fractionation studies showed that trough/MIC and not Time above MIC was the index for amoxicillin that was linked to successful outcome through resistance prevention. Failure of amoxicillin regimens was due to inducible or stable high level expression of β-lactamases. Studies with dicloxacillin demonstrated that Time above MIC of ≥94% was linked with treatment success when BA beta-lactamase activity was negated. Recursive partitioning analysis showed that amoxicillin regimens that produced peak concentrations of <10.99 μg/mL and troughs of >1.75 μg/mL provided a 100% success rate. Other amoxicillin peak and trough values produced success rates of 28-67%. For postpartum and pregnant women and children, Monte Carlo simulations predicted success rates for amoxicillin 1 g q8h of 53, 33, and 44% (30 mg/kg q8h), respectively.
Conclusion:
Amoxicillin is suboptimal for postexposure prophylaxis of BA in pregnant and postpartum women and in children.
FOOTNOTES
* Contact Information: Arnold Louie, M.D., Institute for Therapeutic Innovation, University of Florida College of Medicine, 6550 Sanger Road, Orlando, FL 32827. Telephone: 1-407-313-7061; Fax: 1-407-313-7096; Email: arnold.louie@medicine.ufl.edu
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
-
------
Hollow Fiber Pharmacodynamic Studies and Mathematical Modeling to Predict the Efficacy of Amoxicillin for Anthrax Postexposure Prophylaxis in Pregnant Women and Children
Arnold Louie, M.D.*, Brian VanScoy, B.S., Weiguo Liu, M.D., Robert Kulawy, B.S. and G.L. Drusano, M.D.
Author Affiliations: Institute for Therapeutic Innovation, University of Florida College of Medicine, 6550 Sanger Road, Orlando, FL, 32827
ABSTRACT
Background:
Amoxicillin is considered an option for postexposure prophylaxis of Bacillus anthracis (BA) in pregnant and postpartum women who are breastfeeding and in children because of the potential toxicities of ciprofloxacin and doxycycline to the fetus and child. The amoxicillin regimen that effectively kills BA and prevents resistance is unknown.
Methods:
Fourteen-day dose-range and dose-fractionation studies were conducted in in vitro pharmacodynamic models to identify the exposure intensity and pharmacodynamic index of amoxicillin that are linked with optimized killing of BA and resistance prevention. Studies with dicloxacillin, a drug resistant to BA β-lactamase, evaluated the role of β-lactamase production on the pharmacodynamic indices for BA killing and resistance prevention.
Results:
Dose-fractionation studies showed that trough/MIC and not Time above MIC was the index for amoxicillin that was linked to successful outcome through resistance prevention. Failure of amoxicillin regimens was due to inducible or stable high level expression of β-lactamases. Studies with dicloxacillin demonstrated that Time above MIC of ≥94% was linked with treatment success when BA beta-lactamase activity was negated. Recursive partitioning analysis showed that amoxicillin regimens that produced peak concentrations of <10.99 μg/mL and troughs of >1.75 μg/mL provided a 100% success rate. Other amoxicillin peak and trough values produced success rates of 28-67%. For postpartum and pregnant women and children, Monte Carlo simulations predicted success rates for amoxicillin 1 g q8h of 53, 33, and 44% (30 mg/kg q8h), respectively.
Conclusion:
Amoxicillin is suboptimal for postexposure prophylaxis of BA in pregnant and postpartum women and in children.
FOOTNOTES
* Contact Information: Arnold Louie, M.D., Institute for Therapeutic Innovation, University of Florida College of Medicine, 6550 Sanger Road, Orlando, FL 32827. Telephone: 1-407-313-7061; Fax: 1-407-313-7096; Email: arnold.louie@medicine.ufl.edu
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
-
------