Infectious Disease · Medical Literature
Temocillin versus carbapenems for bacteraemia due to third-generation cephalosporin-resistant Enterobacterales in Spain (ASTARTÉ): a multicentre, phase 3, open-label, non-inferiority, randomised clinical trial.
Abstract
Alternatives to carbapenems for the treatment of third-generation cephalosporin-resistant Enterobacterales (3GCR-E) are urgently needed to reduce the selection pressure posed by these drugs. Temocillin is a neglected narrow-spectrum β-lactam. The aim of the trial was to investigate if temocillin is non-inferior to carbapenems for the targeted treatment of bacteraemia due to 3GCR-E. This multicentre, phase 3, open-label, non-inferiority, randomised, pragmatic, investigator-initiated clinical trial was conducted in 29 Spanish hospitals. We randomly assigned patients with bacteraemia caused by 3GCR-E to receive intravenous temocillin (2 g every 8 h) or meropenem (1 g every 8 h; or ertapenem [1 g per day] if appropriate). Patients aged 18 years or older were eligible if they had monomicrobial bacteraemia due to any 3GCR-E that was susceptible to meropenem and temocillin and treatment for at least 4 days with an active intravenous drug was considered necessary. Randomisation (1:1) was stratified according to previous active drug and to source of infection; no blocks were used. The primary endpoint was clinical success (clinical cure, no need to stop or change the study drug because of adverse event or clinical failure, absence of recurrence, and survival by day 28) in all randomly assigned patients who received at least one dose of a study drug (modified intention-to-treat population [mITT]). Adverse events were assessed in the mITT population. No missing data were reported. A 10% non-inferiority margin was established. The trial was registered in ClinicalTrials.gov (NCT04478721) and is complete and closed to new participants. 334 eligible patients were enrolled between Dec 15, 2020, and Nov 29, 2024, of whom 328 were included in the mITT population (163 assigned temocillin and 165 assigned carbapenems). In 328 participants, the median age was 72 years (IQR 65-80), 106 (32%) were female, 222 (68%) were male, and the median Charlson Comorbidity Index was 2 (IQR 0-4). In the mITT population, clinical success occurred in 120 (74%) of 163 patients assigned temocillin and 121 (73%) of 165 patients assigned carbapenems (difference 0·3% [95% CI -7·7 to ∞]; non-inferiority p=0·017). Serious adverse events were reported in 31 (19%) of 163 patients assigned temocillin and 35 (24%) of 165 patients assigned carbapenems. In patients with bacteraemia caused by 3GCR-E, temocillin was non-inferior to carbapenems as targeted treatment. These findings support the use of temocillin as an effective and safe alternative to carbapenems in this setting. Instituto de Salud Carlos III.
Clinical relevance
In adults with monomicrobial bacteraemia caused by third-generation cephalosporin-resistant Enterobacterales (3GCR-E) susceptible to both agents, is intravenous temocillin non-inferior to carbapenems (meropenem or ertapenem) as targeted therapy with respect to clinical success at day 28? __SNAPSHOT__ {"studyDesign":"Multicentre, phase 3, open-label, non-inferiority, randomised clinical trial (pragmatic, investigator-initiated)","setting":"29 Spanish hospitals; December 15, 2020 – November 29, 2024","sampleSize":"n=334 enrolled; n=328 in modified intention-to-treat (mITT) population (temocillin: n=163, carbapenems: n=165)","population":"Adults (≥18 years) with monomicrobial bacteraemia due to 3GCR-E susceptible to both meropenem and temocillin requiring ≥4 days of active intravenous therapy. Median age 72 years (IQR 65–80); 32% female, 68% male; median Charlson Comorbidity Index 2 (IQR 0–4). Predominantly Western European ethnicity.","intervention":"Intravenous temocillin 2 g every 8 hours","comparator":"Intravenous meropenem 1 g every 8 hours, or ertapenem 1 g once daily if clinically appropriate","primaryOutcome":"Clinical success at day 28 in the mITT population, defined as clinical cure, no need to stop or change the study drug due to adverse event or clinical failure, absence of recurrence, and survival by day 28","followUp":"28 days (primary endpoint); treatment duration 7–14 days","fundingSource":"Government (Instituto de Salud Carlos III / ISCIII; Spanish Network for Research in Infectious Diseases [REIPI]); investigator-initiated; no industry sponsorship reported"}
Key findings
In the mITT population (n=328), clinical success occurred in 120/163 patients (74%) in the temocillin group and 121/165 patients (73%) in the carbapenem group (absolute difference +0.3% [95% CI –7.7% to ∞]; non-inferiority p=0.017), meeting the pre-specified 10% non-inferiority margin. NNT cannot be calculated from a non-inferiority trial demonstrating equivalence; the point estimate difference of 0.3% favoring temocillin is not clinically meaningful. Serious adverse events were reported in 31/163 patients (19%) receiving temocillin and 35/165 patients (24%) receiving carbapenems; no statistically significant difference between groups was reported, though numerically more total adverse events occurred with temocillin. No missing data were reported. This is the first randomised controlled trial to demonstrate non-inferiority of any agent to carbapenems for bacteraemia caused by 3GCR-E; prior trials of piperacillin–tazobactam and fosfomycin failed to demonstrate non-inferiority.
Practice implications
ASTARTÉ establishes, for the first time by RCT, that temocillin (2 g IV q8h) is non-inferior to carbapenems for the targeted treatment of bacteraemia caused by 3GCR-E in adults, with a comparable serious adverse event profile. The approximately 74% clinical success rate in both arms reflects the real-world complexity of this patient population (elderly, high comorbidity burden). The findings apply to patients with confirmed monomicrobial 3GCR-E bacteraemia in whom both temocillin and meropenem susceptibility have been established — they do not apply to empirical therapy, polymicrobial bacteraemia, isolates not susceptible to temocillin, or non-bacteraemic infections. Geographic generalizability is limited by single-country (Spain) enrollment and predominantly Western European ethnicity, and external validity to regions with different 3GCR-E epidemiology (e.g., high-prevalence NDM producers) is uncertain. The clinical importance of these findings is substantial from an antimicrobial stewardship perspective: temocillin is a narrow-spectrum agent whose use instead of broad-spectrum carbapenems may reduce selection pressure for carbapenem-resistant organisms. Since only the abstract was available for review, granular subgroup data, per-protocol analyses, individual component outcomes of the composite endpoint, and organism-level susceptibility distributions cannot be assessed. __LIMITATIONS__ Open-label design: blinding was not feasible because the carbapenem comparator arm included two drugs with different dosing schedules; this introduces potential for assessment bias in subjective outcome components.,Single-country study conducted exclusively in Spain, with predominantly Western European ethnicity, limiting generalizability to other geographic and epidemiological contexts.,Composite primary endpoint (clinical success) combines heterogeneous outcome components; decomposition of the composite into individual components is not available from the abstract.,Median treatment duration was reported to be slightly longer than supported by current evidence for bacteraemia management, which may affect internal validity and real-world applicability.,Temocillin is approved only in a limited number of countries (Belgium, UK), constraining immediate international applicability.,The non-inferiority design and margin (10%) were pre-specified and met, but a 10% absolute margin may be considered clinically generous by some standards.,Randomisation was unstratified (no blocks used), which may introduce imbalance in small subgroups.,Organism-level subgroup analyses (e.g., ESBL vs. AmpC producers, E. coli vs. Klebsiella) and source-of-infection subgroups are not assessable from the abstract alone.,Population was elderly with high comorbidity burden; results may not directly apply to younger or less comorbid patients.,Only abstract available for full critical appraisal. __BOTTOM_LINE_CATEGORY__ practice_changing __BOTTOM_LINE__ The ASTARTÉ trial is the first phase 3 RCT to demonstrate non-inferiority of a non-carbapenem agent — temocillin 2 g IV q8h — to carbapenems for targeted treatment of 3GCR-E bacteraemia, achieving 74% clinical success in both arms with a comparable serious adverse event profile. For clinicians in countries where temocillin is available, these data provide the highest-quality evidence to date supporting its use as a carbapenem-sparing strategy in confirmed, susceptible 3GCR-E bacteraemia. Practice change is justified where temocillin is accessible and susceptibility is confirmed, but availability constraints and the need for organism-level susceptibility testing before use are critical caveats.