Targeted ‘knock out’ therapy with a combination antimicrobial regimen restores treatment options in the management of extensively drug-resistant carbapenemase-producing organisms

<b>Introduction.</b> Cefiderocol (FDC) and the combination of ceftazidime-avibactam and aztreonam (CZA+ATM) are emerging therapeutic options to combat carbapenemase-producing organisms (CPOs) that exhibit resistance due to multiple <i>β</i>-lactamases.<b>Hypothesis/Gap Statement.</b> Molecular diagnostics and specialized antimicrobial susceptibility testing (AST) are infrequently available in most clinical laboratories, and outputs from reference laboratories are not always timely. Practical methods must be explored to provide meaningful advice to treat infections due to CPOs in real time.<b>Aim.</b> To evaluate the <i>in vitro</i> efficacy of FDC and CZA+ATM against CPOs and to compare colistin (CST) MICs obtained locally with those from the reference laboratory.<b>Methodology.</b> CPOs isolated from 2017 to 2023 inclusive were retrieved. AST for FDC was performed using disc diffusion, CZA and ATM individually by E-tests and the E-test superposition method for the combination CZA+ATM. CST AST was performed locally using the VITEK2 system, and MICs were compared with those attained from the reference laboratory where manual broth microdilution is performed.<b>Results.</b> Fifty-eight CPOs were analysed. OXA-48 was the most frequently detected carbapenemase (37.9%, <i>n</i>=22). Co-existing <i>β</i>-lactamases of Ambler classes A and C were present for 79.3% of CPOs (<i>n</i>=46). Twenty-nine isolates (50%) were found to be susceptible to FDC. Fifty-seven isolates (98.3%) were susceptible to CST according to the VITEK2, compared to 44 of 47 tested isolates (93.6%) by the reference broth microdilution. Essential agreement was found to be 78.7%, and categorical agreement was 91.5% with one major error and three very major errors (VMEs) reported. CZA+ATM was tested against 26 CPOs, all of which harboured metallo-<i>β</i>-lactamases. Synergy was detected for all except one isolate where additivity was noted. Of the 32 isolates where combination therapy was not assessed, 29 (90.6%) possessed serine-<i>β</i>-lactamases and were susceptible to CZA monotherapy, whilst three (9.4%) possessed an isolated metallo-<i>β</i>-lactamase and were susceptible to ATM monotherapy.<b>Conclusions.</b> FDC appears to perform favourably against CPOs harbouring serine-<i>β</i>-lactamases, but not metallo-<i>β</i>-lactamases. The VITEK2 may provide presumptive categorical information for CST susceptibility, but MICs must be confirmed by broth microdilution as VMEs can lead to treatment failures. Moreover, our study confirms potent <i>in vitro</i> activity of CZA+ATM against CPOs expressing multiple <i>β</i>-lactamases.