?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F39045%2F&rft.title=In+Vitro+Susceptibility+of+Multidrug-resistant+Pseudomonas+Aeruginosa+Following+Treatment-Emergent+Resistance+to+Ceftolozane-Tazobactam&rft.creator=Rubio%2C+Abigail&rft.description=Background%3A+Multidrug-resistant+(MDR)+Pseudomonas+aeruginosa+is+a+major+public+health+threat.+Treatment+with+ceftolozane-tazobactam+improves+patient+outcomes+compared+to+salvage+therapy%3B+however%2C+resistance+has+emerged+in+~15%25+of+patients+following+courses+ranging+from+7+to+53+days.+Understanding+the+development+and+mechanisms+of+resistance+in+these+difficult+to+treat+MDR+P.+aeruginosa+has+public+health+importance.+Our+objective+was+to+study+the+in+vitro+activity+of+alternative+%CE%B2-lactams+in+the+setting+of+ceftolozane-tazobactam+resistance.+++%0D%0AMethods%3A+Isolates+from+23+patients+in+whom+ceftolozane-tazobactam+resistance+emerged+were+selected+for+analysis.+Minimum+inhibitory+concentrations+(MICs)+were+determined+by+standard+broth+microdilution+in+triplicate+and+interpreted+by+CLSI+breakpoints.+Mechanisms+of+resistance+and+relatedness+of+isolates+were+explored+through+whole-genome+sequence+(WGS)+analysis+in+15+patients+from+whom+baseline+and+post-treatment+isolates+were+available.++%0D%0AResults%3A+23+baseline+and+32+post-treatment+isolates+were+included.+The+median+baseline+ceftolozane-tazobactam+MIC+was+2+%C2%B5g%2FmL+(range%3A+0.5+%E2%80%93+8+%C2%B5g%2FmL).+75%25%2C+25%25%2C+82.6%25%2C+and+83.3%25+of+baseline+isolates+were+non-susceptible+to+ceftazidime%2C+ceftazidime-avibactam%2C+imipenem%2C+and+piperacillin-tazobactam+respectively.+Following+a+median+16+(range%3A+3-+60)+days+of+therapy%2C+the+median+post-exposure+ceftolozane-tazobactam+MIC+was+64+%C2%B5g%2FmL+(range%3A+8+%E2%80%93+%3E256+%C2%B5g%2FmL).++100%25%2C+72.7%25%2C+69.6%25%2C+and+79.2%25+of+post-treatment+isolates+were+resistant+to+ceftazidime%2C+ceftazidime-avibactam%2C+imipenem%2C+and+piperacillin-tazobactam.+The+corresponding+MIC+foldchanges+were+4%2C+8%2C+-2%2C+and+0%2C+respectively.+Median+imipenem-relebactam+MICs+did+not+change+before+or+after+treatment+with+ceftolozane-tazobactam+(median%3D+2+%C2%B5g%2FmL+for+both)+and+16.7%25+were+classified+as+resistant.+WGS+data+revealed+several+mutations+in+ampC+and+ampR+sequences.++Discussion%3A+Our+findings+show+that+resistance+to+ceftolozane-tazobactam+impacts+the+susceptibility+of+alternative+%CE%B2-lactams.+Cross+resistance+occurs+with+ceftazidime+and+ceftazidimeavibactam+(median+4+and+8+fold+MIC+increase%2C+respectively).++Imipenem+MICs+are+decreased+2fold+potentially+demonstrating+collateral+sensitivity.++Piperacillin-tazobactam+MICs+were+unchanged+and+isolates+remained+resistant.+Importantly%2C+imipenem-relebactam+MICs+were+unchanged+suggesting+the+mechanism+of+ceftolozane-tazobactam+resistance+may+be+due+to+structural+changes+in+ampC.++WGS+data+showed+a+number+of+different+mutations+in+both+ampC+and+ampR.+Certain+mutations%2C+such+as+F147L+and+mutations+found+in+positions+234-244%2C+were+found+to+promote+resistance+to+ceftolozane-tazobactam.&rft.date=2020-07-31&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F39045%2F1%2FRubio_AM_MPHThesis_4_2020.pdf&rft.identifier=++Rubio%2C+Abigail++(2020)+In+Vitro+Susceptibility+of+Multidrug-resistant+Pseudomonas+Aeruginosa+Following+Treatment-Emergent+Resistance+to+Ceftolozane-Tazobactam.++Master's+Thesis%2C+University+of+Pittsburgh.++++(Unpublished)++