Molecular Surveillance and Assessment of Ceftolozane/Tazobactam Resistance with Common β-Lactam Antibiotics and β-Lactamase Genes

Ceftolozane/tazobactam (c/t) is a potent β-lactam antibiotic which combines the fifth generation cephalosporin ceftolozane and tazobactam, a β-lactamase inhibitor. The c/t combination therapy was approved in 2014 for the treatment of multidrug resistant (MDR) Enterobacteriaceae, especially intra-abdominal and urinary tract infections. The aim of this study is to assess c/t activity and to examine the association of c/t resistance with four common β-lactamase resistance genes found in clinical Enterobacteriaceae isolates collected from mainly urinary tract infections in an agricultural region in California (USA) between 2013-2020. We tested 993 Extended Spectrum β-lactamases (ESBL) producing Enterobacteriaceae isolates (885 E. coli, 94 K. pneumoniae, 14 other) for c/t susceptibility by Kirby-Bauer disk diffusion and screened using PCR for four common resistance genes with β-lactamase activity(blaTEM, blaOXA, blaSHV, and blaCTX-M) for 855 of the isolates. We also investigated co-resistance of c/t and nine other β-lactam antibiotics. We found that most isolates were susceptible to c/t (58.3%), while 38.5% showed intermediate resistance, and 3.2% were resistant. We also found that K. pneumoniae isolates were more resistant to c/t than E. coli isolates, and that c/t may be a good alternative to carbapenems, in that that some carbapenem resistant isolates were susceptible to c/t. Genotypic analysis showed blaSHV and blaCTX-M are independently associated with elevated c/t resistance. Although c/t demonstrated strong activity against Enterobacteriaceae, the high percentage of isolates with intermediate susceptibility emphasizes the need for close monitoring and continued surveillance for c/t resistance among ESBLs