Vincent H Tam1,2,3, Henrietta Abodakpi2, Weiqun Wang1, Kimberly R Ledesma1, Paul R Merlau1, Katrina Chan2, Rachel Altman3, Truc T Tran4,5, Michael Nikolaou3, Amelia K Sofjan1. 1. Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, USA. 2. Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, USA. 3. Department of Chemical and Biomolecular Engineering, University of Houston Cullen College of Engineering, Houston, TX, USA. 4. Center for Antimicrobial Resistance and Microbial Genomics, University of Texas McGovern Medical School, Houston, TX, USA. 5. Division of Infectious Diseases, University of Texas McGovern Medical School, Houston, TX, USA.
Abstract
OBJECTIVES: Reduced in vitro β-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of β-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a β-lactamase inhibitor. We evaluated different β-lactam/β-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria. METHODS: Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating β-lactamase inhibitor (tazobactam or avibactam) concentrations on β-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of β-lactam/β-lactamase inhibitor combinations was predicted using %T>MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning. RESULTS: A concentration-dependent reduction in β-lactam MIC was observed (r2 ≥0.93). Regrowth could be suppressed in all six experiments using %T>MICi ≥73.6%, but only one out of six experiments below the threshold (P = 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam. CONCLUSIONS: A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected β-lactam/β-lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.
OBJECTIVES: Reduced in vitro β-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of β-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a β-lactamase inhibitor. We evaluated different β-lactam/β-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria. METHODS: Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating β-lactamase inhibitor (tazobactam or avibactam) concentrations on β-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of β-lactam/β-lactamase inhibitor combinations was predicted using %T>MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning. RESULTS: A concentration-dependent reduction in β-lactam MIC was observed (r2 ≥0.93). Regrowth could be suppressed in all six experiments using %T>MICi ≥73.6%, but only one out of six experiments below the threshold (P = 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam. CONCLUSIONS: A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected β-lactam/β-lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.
Authors: V H Tam; A Louie; T R Fritsche; M Deziel; W Liu; D L Brown; L Deshpande; R Leary; R N Jones; G L Drusano Journal: J Infect Dis Date: 2007-05-02 Impact factor: 5.226
Authors: Vincent H Tam; Kai-Tai Chang; Jian Zhou; Kimberly R Ledesma; Kady Phe; Song Gao; Françoise Van Bambeke; Ana María Sánchez-Díaz; Laura Zamorano; Antonio Oliver; Rafael Cantón Journal: J Antimicrob Chemother Date: 2017-05-01 Impact factor: 5.790
Authors: Nobumitsu Tominaga; Timi Edeki; James Li; Maria Learoyd; M René Bouw; Shampa Das Journal: J Infect Chemother Date: 2015-04-28 Impact factor: 2.211
Authors: Tze-Peng Lim; Kimberly R Ledesma; Kai-Tai Chang; Jing-Guo Hou; Andrea L Kwa; Michael Nikolaou; John P Quinn; Randall A Prince; Vincent H Tam Journal: Antimicrob Agents Chemother Date: 2008-05-27 Impact factor: 5.191
Authors: Andrei Zidaru; Brianna M Eales; Weiqun Wang; Paul R Merlau; Todd M Lasco; Amelia K Sofjan; Vincent H Tam Journal: J Glob Antimicrob Resist Date: 2020-11-06 Impact factor: 4.035
Authors: Brianna M Eales; Cole S Hudson; Iordanis Kesisoglou; Weiqun Wang; Michael Nikolaou; Vincent H Tam Journal: Antibiotics (Basel) Date: 2021-10-16