Resistance profiles of carbapenemase-producing Enterobacterales in a large centre in England: are we already losing cefiderocol?

Abstract

Background: Carbapenemase-producing Enterobacterales (CPE) pose difficult therapeutic challenges. We aimed to characterize antimicrobial resistance profiles of CPE in our centre.

Methods: All non-duplicate CPE isolates between 1 August 2020 and 31 August 2023 in a large teaching trust in England were retrospectively studied. Cefiderocol antimicrobial susceptibility testing (AST) was performed using disc diffusion, ceftazidime/avibactam using disc diffusion and gradient diffusion, and ceftazidime/avibactam aztreonam synergy using the double disc diffusion method. EUCAST version 14.0 breakpoints were used.

Results: A total of 158 CPE from 136 patients were isolated. Most patients were colonized with CPE, but only 16.9% had active infections. Thirty-day all-cause mortality was 10.3%, increasing to 13% for patients with infections and to 18.2% for bacteraemias. OXA-48 was the most prevalent carbapenemase (48.1%), followed by NDM (38%). All isolates exhibited MDR profiles, with high levels of resistance to meropenem (41.1%). Resistance to cefiderocol was found in 69.7% of NDM-producing isolates, with a further 18.2% in the area of technical uncertainty. Ceftazidime/avibactam and aztreonam synergy was seen in 87.5% of isolates, whereas colistin and fosfomycin susceptibility remained high (98.1% and 97.2%, respectively). All OXA-48-producing isolates were susceptible to ceftazidime/avibactam, and 15.3% were resistant to cefiderocol. No patients had been exposed to cefiderocol beforehand, whereas three had been exposed to ceftazidime/avibactam. The most common risk factor for CPE isolation was travel and receiving healthcare abroad, especially in Asia.

Conclusions: We found high rates of resistance to cefiderocol in CPE isolates without prior cefiderocol exposure. Our results prohibit empirical use of cefiderocol for the treatment of CPE infections in our setting.

Figure 1.

AST results of study isolates. (a) All isolates (N = 158); (b) NDM-producing and NDM- and OXA-48-producing isolates (n = 72); (c) OXA-48-producing isolates (n = 76). Numbers represent percentages of all tested isolates for that antimicrobial and do not take into account non-tested isolates. Ceftazidime/avibactam and aztreonam S and R represent presence or absence of in vitro synergy, respectively, rather than formal susceptibility breakpoints. AMK, amikacin; ATM, aztreonam; CAZ, ceftazidime; CIP, ciprofloxacin; CRO, ceftriaxone; CST, colistin; CZA, ceftazidime/avibactam; CZA & ATM, ceftazidime/avibactam and aztreonam; ETP, ertapenem; FDC, cefiderocol; FEP, cefepime; FOF, fosfomycin; GEN, gentamicin; I, susceptible, increased exposure; IPM, imipenem; MEC, mecillinam; MEM, meropenem; NIT, nitrofurantoin; R, resistant; S, susceptible; SXT, trimethoprim/sulfamethoxazole; TGC, tigecycline; TMC, temocillin; TZP, piperacillin/tazobactam; U, area of technical uncertainty. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Cefiderocol disc diffusion diameter results for (a) all study isolates (N = 113); (b) NDM-producing and NDM- and OXA-48-producing isolates (n = 66); and (c) OXA-48-producing isolates (n = 39), according to 2024 EUCAST breakpoints version 14.0. 2023 FDA/CLSI breakpoints are also shown for comparison. Green: susceptible; Orange: area of technical uncertainty; Red: resistant. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Risk factors for carbapenemase-producing Enterobacterales isolation in study patients (N = 136). Univariable comparisons of categorical variables were made using Pearson’s chi-squared test; 95% CIs were calculated using 10 000 bootstrap samples; *P = 0.04. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.