Infectious Disease · Medical Literature
[Articles] 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
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.
Clinical relevance
In hospitalized adults with monomicrobial bacteraemia caused by third-generation cephalosporin-resistant Enterobacterales (3GCR-E), is targeted treatment with intravenous temocillin non-inferior to carbapenems in achieving clinical success by day 28? __SNAPSHOT__ {"studyDesign":"Phase 3, multicentre, open-label, non-inferiority, randomised controlled trial (pragmatic, investigator-initiated)","setting":"29 Spanish hospitals; conducted December 15, 2020 – November 29, 2024","sampleSize":"n=334 enrolled; n=328 in the modified intention-to-treat (mITT) population (temocillin: n=163; carbapenems: n=165)","population":"Adults ≥18 years with monomicrobial bacteraemia due to any 3GCR-E susceptible to both meropenem and temocillin, requiring at least 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; randomisation 1:1 stratified by prior active drug and source of infection","primaryOutcome":"Clinical success at day 28 in the mITT population, defined as clinical cure, no need to stop or change study drug due to adverse event or clinical failure, absence of recurrence, and survival by day 28","followUp":"28 days","fundingSource":"Government (Instituto de Salud Carlos III / ISCIII; conducted within the Spanish Network for Research in Infectious Diseases, REIPI); investigator-initiated; no industry funding reported"}
Key findings
In the mITT population (n=328), clinical success occurred in 120/163 (74%) patients in the temocillin group and 121/165 (73%) in the carbapenem group — an absolute risk difference of 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 these data as the comparison did not establish superiority. Serious adverse events were reported in 31/163 (19%) patients receiving temocillin versus 35/165 (24%) receiving carbapenems; while numerically fewer serious adverse events occurred with temocillin, the difference was not reported as statistically significant. Overall adverse event rates were numerically higher with temocillin, though severe adverse event rates did not differ significantly between arms. No missing data were reported. The overall median duration of therapy was slightly longer than that supported by recent evidence for bacteraemia management (specific duration not reported in available abstract). Treatment was between 7 and 14 days per protocol, with sequential oral therapy permitted from day 5 onward if appropriate.
Practice implications
The ASTARTÉ trial is the first randomised controlled trial to demonstrate that temocillin is non-inferior to carbapenems for the targeted treatment of bacteraemia due to 3GCR-E, filling a critical evidence gap — prior randomised trials of piperacillin-tazobactam and fosfomycin both failed to demonstrate non-inferiority versus meropenem in this setting. The non-inferiority finding is clinically meaningful given the urgent need for carbapenem-sparing strategies to limit selection pressure for carbapenem-resistant organisms. The findings apply to adults with monomicrobial 3GCR-E bacteraemia who are susceptible to both temocillin and meropenem and require intravenous therapy; they do not apply to polymicrobial bacteraemia, infections due to carbapenem-resistant organisms, or organisms not susceptible to temocillin. The study population was predominantly elderly, predominantly male, and of Western European ethnicity from a single country, limiting direct generalisability to other healthcare systems, geographic regions, and patient demographics. Temocillin is a narrow-spectrum β-lactam stable against ESBLs and AmpC enzymes; its use in lieu of carbapenems could meaningfully reduce ecological collateral damage and the spread of carbapenem resistance. Importantly, this summary is based on the published abstract only — full data on specific infection sources, causative Enterobacterales species distribution, rates of ESBL vs. AmpC mechanisms, individual adverse event profiles, duration of therapy, and any pharmacokinetic substudies are not available in this analysis. Clinical implementation is also constrained by temocillin's limited regulatory approval (currently authorized in only a few countries, not routinely available in Spain without investigational access). __LIMITATIONS__ Open-label design (blinding not feasible given the two-drug carbapenem comparator arm with differing dosing schedules), introducing potential performance and detection bias in composite clinical outcome assessment.,Single-country study (Spain) with predominantly Western European patients, limiting generalisability to other geographic regions and healthcare settings with differing resistance epidemiology.,Non-inferiority design cannot establish superiority; the one-sided 95% CI lower bound of −7.7% approaches but does not cross the −10% non-inferiority margin, leaving uncertainty about the true magnitude of the treatment difference.,The pre-specified 10% non-inferiority margin is relatively wide; a 7.7% absolute difference in clinical success would be clinically meaningful in bacteraemia management.,Composite primary endpoint (clinical success) includes subjective components (clinical cure, stopping/changing due to adverse event), which may be differentially assessed in an open-label setting.,Treatment duration (7–14 days) may be longer than recommended by contemporary evidence for bacteraemia management, potentially affecting both efficacy and safety outcome rates.,Temocillin is not licensed in most countries, including Spain (used under investigational status), limiting immediate clinical applicability outside of health systems where it is commercially available.,Restriction to patients susceptible to both temocillin and meropenem introduces selection bias — organisms resistant to temocillin (which can occur) were excluded, and the proportion of screened patients excluded on this basis is not available in the abstract.,The abstract does not report species-level or resistance-mechanism breakdown (ESBL vs. AmpC), precluding subgroup interpretation.,No missing data reported — the mechanism of handling missing outcomes or withdrawals is unclear from the abstract alone. __BOTTOM_LINE_CATEGORY__ practice_changing __BOTTOM_LINE__ The ASTARTÉ trial provides the first high-quality randomised evidence that intravenous temocillin (2 g q8h) is non-inferior to carbapenems for targeted treatment of 3GCR-E bacteraemia in adults, with a comparable serious adverse event profile. This finding supports temocillin as a clinically viable carbapenem-sparing alternative in patients whose isolates are susceptible to temocillin, though widespread uptake is currently limited by temocillin's restricted regulatory availability. Where temocillin is accessible, clinicians managing 3GCR-E bacteraemia in appropriate patients now have randomised evidence to justify its use as a targeted therapy.