Pranita D Tamma1, Stephan Beisken2, Yehudit Bergman3, Andreas E Posch4, Edina Avdic5, Sima L Sharara6, Sara E Cosgrove7, Patricia J Simner8. 1. Johns Hopkins University School of Medicine, Department of Pediatrics, Division of Pediatric Infectious Diseases, Baltimore, Maryland USA. 2. Ares Genetics, Head of Bioinformatics & Analytics, Vienna, Austria. 3. Johns Hopkins University School of Medicine, Department of Pathology, Baltimore, Maryland, USA. 4. Ares Genetics, Chief Executive Officer, Vienna, Austria. 5. Johns Hopkins Hospital, Department of Pharmacy, Baltimore, Maryland, USA. 6. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 7. Johns Hopkins University School of Medicine, Department of Medicine, Baltimore, Maryland, USA. 8. Johns Hopkins University School of Medicine, Department of Pathology, Division of Medical Microbiology, Baltimore, Maryland, USA.
Abstract
BACKGROUND: Ceftolozane-tazobactam (TOL-TAZ) affords broad coverage against Pseudomonas aeruginosa. Regrettably, TOL-TAZ resistance has been reported. We sought to identify modifiable risk factors that may reduce the emergence of TOL-TAZ resistance. METHODS: Twenty-eight consecutive patients infected with carbapenem-resistant P. aeruginosa isolates susceptible to TOL-TAZ, treated with ≥72 hours of TOL-TAZ , and with P. aeruginosa isolates available both before and after TOL-TAZ exposure between January 2018 and December 2019 in Baltimore, Maryland, were included. Cases were defined as patients with at least a 4-fold increase in P. aeruginosa TOL-TAZ MICs after exposure to TOL-TAZ. Independent risk factors for the emergence of TOL-TAZ resistance comparing cases and controls were investigated using logistic regression. Whole genome sequencing of paired isolates was used to identify mechanisms of resistance that emerged during TOL-TAZ therapy. RESULTS: Fourteen patients (50%) had P. aeruginosa isolates which developed at least a 4-fold increase in TOL-TAZ MICs(ie, cases). Cases were more likely to have inadequate source control (29% vs 0%, P = .04) and were less likely to receive TOL-TAZ as an extended 3-hour infusion (0% vs 29%; P = .04). Eighty-six percent of index isolates susceptible to ceftazidime-avibactam (CAZ-AVI) had subsequent P. aeruginosa isolates with high-level resistance to CAZ-AVI, after TOL-TAZ exposure and without any CAZ-AVI exposure. Common mutations identified in TOL-TAZ resistant isolates involved AmpC, a known binding site for both ceftolozane and ceftazidime, and DNA polymerase. CONCLUSIONS: Due to our small sample size, our results remain exploratory but forewarn of the potential emergence of TOL-TAZ resistance during therapy and suggest extending TOL-TAZ infusions may be protective. Larger studies are needed to investigate this association.
BACKGROUND: Ceftolozane-tazobactam (TOL-TAZ) affords broad coverage against Pseudomonas aeruginosa. Regrettably, TOL-TAZ resistance has been reported. We sought to identify modifiable risk factors that may reduce the emergence of TOL-TAZ resistance. METHODS: Twenty-eight consecutive patients infected with carbapenem-resistant P. aeruginosa isolates susceptible to TOL-TAZ, treated with ≥72 hours of TOL-TAZ , and with P. aeruginosa isolates available both before and after TOL-TAZ exposure between January 2018 and December 2019 in Baltimore, Maryland, were included. Cases were defined as patients with at least a 4-fold increase in P. aeruginosa TOL-TAZ MICs after exposure to TOL-TAZ. Independent risk factors for the emergence of TOL-TAZ resistance comparing cases and controls were investigated using logistic regression. Whole genome sequencing of paired isolates was used to identify mechanisms of resistance that emerged during TOL-TAZ therapy. RESULTS: Fourteen patients (50%) had P. aeruginosa isolates which developed at least a 4-fold increase in TOL-TAZ MICs(ie, cases). Cases were more likely to have inadequate source control (29% vs 0%, P = .04) and were less likely to receive TOL-TAZ as an extended 3-hour infusion (0% vs 29%; P = .04). Eighty-six percent of index isolates susceptible to ceftazidime-avibactam (CAZ-AVI) had subsequent P. aeruginosa isolates with high-level resistance to CAZ-AVI, after TOL-TAZ exposure and without any CAZ-AVI exposure. Common mutations identified in TOL-TAZ resistant isolates involved AmpC, a known binding site for both ceftolozane and ceftazidime, and DNA polymerase. CONCLUSIONS: Due to our small sample size, our results remain exploratory but forewarn of the potential emergence of TOL-TAZ resistance during therapy and suggest extending TOL-TAZ infusions may be protective. Larger studies are needed to investigate this association.
Authors: Alba Ruedas-López; Isaac Alonso-García; Cristina Lasarte-Monterrubio; Paula Guijarro-Sánchez; Eva Gato; Juan Carlos Vázquez-Ucha; Juan Andrés Vallejo; Pablo Arturo Fraile-Ribot; Begoña Fernández-Pérez; David Velasco; José María Gutiérrez-Urbón; Marina Oviaño; Alejandro Beceiro; Concepción González-Bello; Antonio Oliver; Jorge Arca-Suárez; Germán Bou Journal: Antimicrob Agents Chemother Date: 2021-12-20 Impact factor: 5.938
Authors: Abigail M Rubio; Ellen G Kline; Chelsea E Jones; Liang Chen; Barry N Kreiswirth; M Hong Nguyen; Cornelius J Clancy; Vaughn S Cooper; Ghady Haidar; Daria Van Tyne; Ryan K Shields Journal: Antimicrob Agents Chemother Date: 2021-05-18 Impact factor: 5.191
Authors: Bryan D Lizza; Kevin D Betthauser; David J Ritchie; Scott T Micek; Marin H Kollef Journal: Antimicrob Agents Chemother Date: 2021-06-17 Impact factor: 5.191
Authors: Patricia J Simner; Jerald Cherian; Gina A Suh; Yehudit Bergman; Stephan Beisken; Joseph Fackler; Martin Lee; Robert J Hopkins; Pranita D Tamma Journal: JAC Antimicrob Resist Date: 2022-05-05
Authors: Patricia J Simner; Stephan Beisken; Yehudit Bergman; Andreas E Posch; Sara E Cosgrove; Pranita D Tamma Journal: Open Forum Infect Dis Date: 2021-06-12 Impact factor: 3.835