Jun Hirai1, Mao Hagihara2, Hideo Kato2, Daisuke Sakanashi3, Naoya Nishiyama4, Yusuke Koizumi4, Yuka Yamagishi4, Hiroyuki Suematsu3, Hideaki Hanaki5, Hiroshige Mikamo6. 1. Department of Clinical Infectious Diseases, Aichi Medical University School of Hospital, Japan; Department of Infection Control and Prevention, Aichi Medical University Hospital, Japan; Department of Infectious, Respiratory, and Digestive Medicine, Control and Prevention of Infectious Diseases, Faculty of Medicine, University of the Ryukyus, Japan. 2. Department of Clinical Infectious Diseases, Aichi Medical University School of Hospital, Japan; Department of Pharmacy, Aichi Medical University School of Hospital, Japan. 3. Department of Infection Control and Prevention, Aichi Medical University Hospital, Japan. 4. Department of Clinical Infectious Diseases, Aichi Medical University School of Hospital, Japan; Department of Infection Control and Prevention, Aichi Medical University Hospital, Japan. 5. Research Center for Infections and Antimicrobials, Kitasato Institute for Life Sciences, Kitasato University, Japan. 6. Department of Clinical Infectious Diseases, Aichi Medical University School of Hospital, Japan; Department of Infection Control and Prevention, Aichi Medical University Hospital, Japan. Electronic address: mikamo@aichi-med-u.ac.jp.
Abstract
BACKGROUND: The purpose of this study was to examine the pharmacokinetics/pharmacodynamics of rifampicin against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and vancomycin-intermediate S. aureus (VISA) in a neutropenic murine thigh infection model. METHODS: Three S. aureus isolates (MSSA [ATCC 25923], MRSA and VISA [Mu50]) with rifampicin MIC 0.06 to >256 μg/mL were tested. The efficacy was calculated as the change in bacterial density. A maximum effect model was used to determine the PK/PD index that best described the dose-response data. RESULTS: The area under the curve (AUC)/MIC and maximum concentration of drug in serum (Cmax/MIC) were the best correlated with in vivo efficacy (AUC/MIC, R(2) = 0.96; Cmax/MIC, R(2) = 0.97) for S. aureus ATCC 25923 strain, and the dose fractionation-response study did not show significantly different antimicrobial activity (p = 0.10). The AUC/MIC values associated with stasis and 1-log kill for the S. aureus ATCC 25923 strain were 386 and 952, respectively. On the other hand, no antimicrobial efficacy was observed against two strains (MRSA and VISA) with MIC of 128 μg/mL or more. CONCLUSION: Rifampicin demonstrated concentration-dependent killing. The AUC/MIC was a predictive PK/PD index.
BACKGROUND: The purpose of this study was to examine the pharmacokinetics/pharmacodynamics of rifampicin against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and vancomycin-intermediate S. aureus (VISA) in a neutropenic murine thigh infection model. METHODS: Three S. aureus isolates (MSSA [ATCC 25923], MRSA and VISA [Mu50]) with rifampicin MIC 0.06 to >256 μg/mL were tested. The efficacy was calculated as the change in bacterial density. A maximum effect model was used to determine the PK/PD index that best described the dose-response data. RESULTS: The area under the curve (AUC)/MIC and maximum concentration of drug in serum (Cmax/MIC) were the best correlated with in vivo efficacy (AUC/MIC, R(2) = 0.96; Cmax/MIC, R(2) = 0.97) for S. aureus ATCC 25923 strain, and the dose fractionation-response study did not show significantly different antimicrobial activity (p = 0.10). The AUC/MIC values associated with stasis and 1-log kill for the S. aureus ATCC 25923 strain were 386 and 952, respectively. On the other hand, no antimicrobial efficacy was observed against two strains (MRSA and VISA) with MIC of 128 μg/mL or more. CONCLUSION:Rifampicin demonstrated concentration-dependent killing. The AUC/MIC was a predictive PK/PD index.
Authors: Brad Spellberg; Gloria Aggrey; Meghan B Brennan; Brent Footer; Graeme Forrest; Fergus Hamilton; Emi Minejima; Jessica Moore; Jaimo Ahn; Michael Angarone; Robert M Centor; Kartikeya Cherabuddi; Jennifer Curran; Kusha Davar; Joshua Davis; Mei Qin Dong; Bassam Ghanem; Doug Hutcheon; Philipp Jent; Minji Kang; Rachael Lee; Emily G McDonald; Andrew M Morris; Rebecca Reece; Ilan S Schwartz; Miranda So; Steven Tong; Christopher Tucker; Noah Wald-Dickler; Erica J Weinstein; Riley Williams; Christina Yen; Shiwei Zhou; Todd C Lee Journal: JAMA Netw Open Date: 2022-05-02