These recommendations are supported by the following data: first, for carbapenem-susceptible bacteria, no randomized controlled trial has shown a superiority of NBs/BIs over meropenem or the best available treatment [
18‐
22]; second, colonization by Gram-negative bacteria resistant to carbapenems due to the production of carbapenemase is currently exceptional. In France, ertapenem-resistant Enterobacterale isolates vary between 0.02 and 0.2% [
23]. A 2019 study in 11 Parisian hospitals found that only 1.2% of patients were colonized with carbapenemase-producing Enterobacteriales [
4]. In an intensive care setting, REA-REZO 2018 data showed that 14.4% of health care-associated infections were attributed to
Pseudomonas aeruginosa, with 23.3% of carbapenem-resistant strains, without specifying the mechanism of resistance [
24]. Moreover,
P. aeruginosa often combines several mechanisms of resistance, including an efflux system or lack of permeability due to porin inactivation, mutations in the penicillin-binding protein, and the overproduction of natural cephalosporinase [
25]. Beta-lactams other than NBs/BIs may be active against all of these mechanisms. Third, less than 10% of patients colonized with multidrug-resistant (MDR) bacteria will develop an infection due to these bacteria, and the absence of colonization by MDR bacteria is an excellent negative predictive factor for MDR bacterial infection [
26‐
28]. Fourth, similar to other beta-lactams, NBs/BIs exert selection pressure. For example, exposure to ceftazidime–avibactam led to the emergence of 20% resistance in Enterobacterales [
7], and exposure to ceftolozane–tazobactam led to 15–50% resistance in
P. aeruginosa [
8,
9]. After exposure to ceftolozane–tazobactam, cross-resistance to ceftazidime–avibactam has also been reported [
9,
10]. Rapid emergence of resistance has been reported with cefiderocol and, in addition, has been associated with excess mortality of patients infected with
Acinetobacter baumannii [
11].
Thus, given the lack of superiority of NBs/BIs over carbapenems, the low risk of MDR bacterial infection in the absence of prior colonization or an ongoing epidemic, the risk of the emergence of resistance, and the need to keep these antibiotics as a last resort, the panel suggests that their empirical use should be reserved for exceptional situations combining septic shock and known colonization by either carbapenem-resistant bacteria or P. aeruginosa resistant to other antipyocyanic antibiotics or in the event of a local epidemic of one of these germs. There are no data to support empirical use of NBs/BIs in the sole presence of risk factors for MDR bacterial colonization. Prior carbapenem therapy is a risk factor for the selection of carbapenem resistance in P. aeruginosa but is not sufficient to support the empirical use of NBs/BIs.
In exceptional cases where empirical administration of one of these antibiotics has been initiated, it is imperative that this therapy be reassessed and reduced if possible. This assumes that bacteriology laboratories reduce the time needed to determine antibiotic susceptibility, and to test available antibiotics without incorporating a priori strategies for sparing certain molecules.