Comment
Temocillin as a carbapenem-sparing option for ESBL bloodstream infection
Sean W X Ong, Nick Daneman
Lancet Available online 9 July 2026
https://doi.org/10.1016/S0140-6736(26)01334-6
Antimicrobial resistance is a global threat to public health, already associated with more than 1 million attributable deaths per year; Enterobacterales, including Escherichia coli, are the pathogens responsible for the largest numbers of these antimicrobial resistance-associated deaths.1 Resistance to third-generation cephalosporins, most commonly mediated by extended-spectrum ß-lactamase (ESBL) production, is rising rapidly2 and is associated with a particularly high incremental risk of death.3 An additional challenge of this resistance profile is that it requires the use of carbapenem treatment, which in turn is generating global increases in carbapenem-resistant organisms for which few treatment options exist. Until now, there has been no carbapenem-sparing option to treat third-generation cephalosporin-resistant Enterobacterales.
In The Lancet, Francesco Cogliati Dezza and colleagues provide evidence in the ASTARTÉ trial that an old narrow-spectrum penicillin, temocillin, could provide one such option.4The investigators conducted a multicentre, phase 3, open-label, non-inferiority, randomised clinical trial of temocillin versus carbapenem (meropenem or ertapenem) among patients with bacteraemia caused by third-generation cephalosporin-resistant Enterobacterales across 29 hospitals in Spain. The ASTARTÉ trial enrolled 334 adult patients with blood cultures positive for Enterobacterales and documented ceftriaxone resistance and temocillin and carbapenem susceptibility for whom the clinical team deemed that a minimum of 4 days and a maximum of 14 days of intravenous treatment were needed for the infection. Randomisation (1:1) was stratified by source of bloodstream infection and previous use of active treatment. The intervention group received temocillin 2 g intravenously every 8 h; the control group received meropenem 1 g intravenously every 8 h or ertapenem 1 g intravenously every 24 h, with a suggested duration of 7–14 days in both groups. The primary endpoint was clinical success, a composite endpoint defined as resolution of all new infection-related signs and symptoms at the test-of-cure visit 7–10 days after treatment, no need to change treatment because of adverse event or clinical failure, no recurrence of bacteraemia with the same organism by day 28, and survival at day 28. The primary analysis was conducted in a modified intention-to-treat population of 328 participants (median age 72 years [IQR 65–80], 106 (32%) were female and 222 (68%) male, and about 90% were of western European ethnicity) who received at least one dose of study drug, and the aim was to show non-inferiority of temocillin with a pre-specified non-inferiority margin of 10%. Clinical success occurred in 120 (74%) of 163 temocillin recipients and 121 (73%) of 165 carbapenem recipients. Therefore, the ASTARTÉ data showed non-inferiority of temocillin (absolute difference 0·3 percentage points [one-sided 95% CI –7·7 to ∞]; non-inferiority p=0·017). Results were consistent in the per-protocol population (those who received at least 3 days of study drug) and the clinically evaluable population (those who were evaluated at test-of-cure visit). Non-inferiority was also met for each individual component of the composite outcome. 31 (19%) of 163 patients in the temocillin group and 35 (24%) of 165 participants in the carbapenem group had severe adverse effects, of which four in the temocillin group and one in the carbapenem group were considered related to treatment.
These results provide robust evidence that temocillin is a safe and viable alternative to carbapenems for the treatment of bacteraemia caused by ESBL-producing Enterobacterales, and the investigators should be congratulated for completing this rigorous and well designed trial. Carbapenem-sparing options are much needed to minimise carbapenem use and the associated selection pressure on carbapenem-resistant organisms, a growing threat around the world and the top-ranked threat on the WHO Bacterial Priority Pathogens List.5
However, there are several important factors to consider when interpreting the results of this trial. First, this trial is of definitive therapy, and patients had a median of 2 days (IQR 1–3) of antibiotic therapy before randomisation. 137 (84%) of 163 patients in the temocillin group received at least one carbapenem dose before randomisation, which could increase the probability of non-inferiority since they might have already received effective therapy during the crucial first 48 h of infection. Other trials of treatment options for third-generation cephalosporin-resistant bacteraemia, such as the MERINO trial and the PeterPen trial, face this issue.6, 7 Trials of empirical therapies are needed, although novel trial design solutions (eg, informed consent waivers with cluster randomisation of institutional empirical treatment guidelines) could have to be used to enrol and randomly assign patients at presentation before availability of microbiology and susceptibility results.
Second, the 28-day mortality rate was low (four [2%] of 163 patients in the temocillin group and six [4%] of 165 patients in the carbapenems group) in this trial compared with what would be expected in the patient population with Gram-negative bacteraemia typically encountered in clinical practice (ranging from 12% to 20% in large observational studies)8, 9 and could be indicative of a selected study cohort with low disease severity. Indeed, median Sequential Organ Failure Assessment score was 2 (IQR 1–3), and 75% of the cohort had a urinary tract source of bacteraemia (generally associated with low severity). The study findings might thus not be generalisable to critically ill patients. Nonetheless, these mortality rates and baseline characteristics are similar to other comparable trials (eg, 3·7% in the meropenem group in the MERINO trial).6
Finally, and most importantly, most clinicians will not be able to immediately implement these results since there is limited access to temocillin—it is currently only licensed for use in several European countries and, crucially, is not available in regions such as Asia and sub-Saharan Africa where ESBL prevalence is the highest.2 Drug manufacturers, regulators, and policy makers should use these results to advocate for expanded access to temocillin for patients who need it the most.
These limitations notwithstanding, the ASTARTÉ trial provides practice-changing evidence that alternative agents other than carbapenems can be used for the treatment of bacteraemia caused by third-generation cephalosporin-resistant Enterobacterales. We hope that these results motivate further well conducted clinical trials that continue to fill this therapeutic gap in our antibiotic armamentarium.
