Emerging β-lactam and β-lactamase inhibitor strategies for complicated urinary

# Emerging β-lactam and β-lactamase inhibitor strategies for complicated urinary tract infections *The Lancet 2026* Comment neurological deterioration versus 81 (12%) of 692 in trial that sharpens the question, suggesting early the placebo group, a nearly 40% relative reduction and platelet inhibition after intravenous thrombolysis might arguably the most biologically suggestive signal in the benefit the phenotype it sampled. Treatment guidelines trial. still withhold antiplatelets for 24 h after thrombolysis Assessment of safety is harder in TAPIS. Symptomatic and do not fully endorse tirofiban.6 TAPIS might not intracranial haemorrhage within 36 h occurred in six change that tomorrow, but it is a key piece of evidence versus five patients (risk ratio 1·20 [95% CI 0·37–3·93); about a specific stroke biology. More such pieces, from the low event rate might not allow a confident safety more regions, are what a mature, global, evidence base inference, especially when the 95% upper bound looks like: biology, not geography, determines where suggests a near four-times increase. Moreover, if benefit lies. the principal benefit of ticagrelor and aspirin were I declare no competing interests. prevention of re-occlusion, one might expect a lower Bijoy K Menon rate of recurrent ischaemic stroke in that group; this bkmmenon@ucalgary.ca was not the case. The rescue-therapy imbalance points Department of Clinical Neurosciences, Department of Radiology, Cumming indirectly towards prevention of early re-thrombosis, School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Community Health Sciences, University of Calgary, Calgary, AB, but without serial vascular imaging, this remains Canada; Hotchkiss Brain Institute, Calgary, AB, Canada inference, not proof. 1 Wang A, Xia X, Tang Y, et al. Ticagrelor with aspirin dual antiplatelet therapy combined with intravenous thrombolysis in patients with ischaemic stroke There is a habit in stroke medicine of treating in China (TAPIS): a multicentre, double-blind, randomised controlled trial. a positive trial from one region as provisional, Lancet 2026; published online May 8. https://doi.org/10.1016/ S0140-6736(26)00757-9. awaiting confirmation in another. That habit is worth 2 Chen HS, Cui Y, Li XQ, et al. Early antiplatelet treatment for minor stroke questioning. TAPIS is not a provisional finding; it is following thrombolysis: the EAST trial. Eur Heart J 2026; 47: 746–56. 3 Zinkstok SM, Roos YB. Early administration of aspirin in patients treated evidence about a specific biology of stroke. As trials with alteplase for acute ischaemic stroke: a randomised controlled trial. Lancet 2012; 380: 731–37. accumulate from more regions, stroke medicine gains 4 Adeoye O, Broderick J, Derdeyn CP, et al. Adjunctive intravenous argatroban a richer map of where treatments work, in whom, and or eptifibatide for ischemic stroke. N Engl J Med 2024; 391: 810–20. why. The goal is not to reduce this heterogeneity to a 5 Tao C, Liu T, Cui T, et al. Early tirofiban infusion after intravenous thrombolysis for stroke. N Engl J Med 2025; 393: 1191–201. single global answer but to act on regional evidence in 6 Prabhakaran S, Gonzalez NR, Zachrison KS, et al., 2026 Guideline for the Early Management of Patients With Acute Ischemic Stroke: A Guideline patients who share the biology such trials sampled. From the American Heart Association/American Stroke Association. Stroke TAPIS should not be read as practice changing, nor as 2026; published online Jan 26. doi:10.1161/STR.0000000000000513. provisional evidence needing replication. It is a positive Emerging β-lactam and β-lactamase inhibitor strategies for complicated urinary tract infections Complicated urinary tract infections (cUTIs) and carbapenem-sparing strategies.³ The phase 3 Integral-1 acute pyelonephritis remain major causes of trial evaluating cefepime–nacubactam and aztreonam– hospitalisation worldwide and contribute substantially nacubactam compared with imipenem–cilastatin, to antibiotic consumption and health-care costs.¹ The presented by Satoshi Takahashi and colleagues in increasing prevalence of antibiotic resistance among The Lancet, represents an important step towards Gram-negative bacterial pathogens, particularly expanding the potential therapeutic arsenal against See Articles page 1929 extended-spectrum β-lactamase (ESBL)-producing non-carbapenem resistant Gram-negative infections.⁴ Enterobacterales and carbapenem-resistant bacteria has Nacubactam is a diazabicyclooctane β-lactamase made effective treatment increasingly challenging.² inhibitor with a distinctive dual mechanism of action. In this context, the development of novel β-lactam Beyond inhibiting several classes of serine β-lactamases and β-lactamase inhibitor combinations aids (class A, class C, and some class D enzymes), nacubactam preservation of treatment options and supports also directly targets penicillin-binding protein 2 in segamI ytteG aiv 16dnetseW Comment Enterobacterales, enhancing the antibacterial activity groups traditionally associated with poorer clinical of partner β-lactams.⁵,⁶ This dual activity differentiates outcomes.²,⁷ Although the study excluded carbapenem- nacubactam from many existing β-lactamase inhibitors resistant pathogens due to the use of imipenem as and might contribute to improved microbiological the comparator, the favourable outcomes in resistant outcomes when combined with agents such as cefepime infections support the hypothesis that nacubactam or aztreonam.⁵ combinations might play an important role in managing The Integral-1 study was a multicentre, double-blind, antimicrobial-resistant Gram-negative infections.³ randomised phase 3 trial conducted across 79 sites in Safety outcomes were reassuring. Treatment- eastern Europe, China, and Japan. 614 patients with emergent adverse events occurred less frequently in cUTIs (66%) or acute pyelonephritis (34%) were both nacubactam groups (30–33%) compared with randomly assigned in a 2:1:1 ratio to receive cefepime– imipenem–cilastatin (43%), and most events were mild nacubactam (n=309), aztreonam–nacubactam or moderate in severity.⁴ The incidence and profile of (n=154), or the comparator imipenem–cilastatin adverse reactions were broadly consistent with those (n=151). In the microbiological modified intention known for cefepime and aztreonam alone, suggesting to treat (mITT) population comprising 431 patients that the addition of nacubactam does not significantly included in the primary efficacy analysis, the mean alter the established safety profiles of these agents.⁶ No age was 64·8 years, 228 patients (53%) were male treatment-related deaths were reported. and 203 (47%) were female, and 368 (85%) were How should these new nacubactam-containing White, with Chinese and Japanese comprising 9% β-lactam and β-lactamase inhibitor combinations be (n=39) and 5% (n=23) respectively. Demographic positioned from an antibiotic stewardship standpoint? characteristics were well matched between groups. The Although the primary endpoint superiority of cefepime– primary endpoint was a composite of clinical cure and nacubactam over imipenem–cilastatin was clear at microbiological eradication at the test-of-cure visit in the test-of-cure visit 5–9 days after end of treatment, the microbiological mITT population. that success was far less impressive at follow-up The results show notable efficacy for the approximately 1 week later: primary endpoint success nacubactam combinations. Cefepime–nacubactam of cefepime–nacubactam, aztreonam–nacubactam, and achieved composite success in 176 (82%) of imipenem–cilastatin was, respectively: 69% (147 of 214), 214 patients compared with 64 (61%) of 105 patients 65% (73 of 112) and 62% (65 of 105); clinical cure: 88% for imipenem–cilastatin, meeting both the predefined (188 of 214), 88% (98 of 112), and 85% (89 of 105); 15% criteria for non-inferiority, and superiority. and microbiological eradication: 73% (157 of 214), 67% Aztreonam–nacubactam achieved a 72% (in 81 of (75 of 112), and 65% (68 of 105). Moreover, recurrence, 112 patients) success rate, showing non-inferiority to defined as the rate of isolation of the same the comparator but was not powered to test superiority. pathogen after an eradication response, at follow- The percentage difference in success rates for cefepime– up was 19% (40 of 214), 26% (29 of 112) and 24% nacubactam and aztreonam–nacubactam compared (25 of 105) respectively, thus showing little difference. with the comparator were 21·3% (95% CI 10·9 to 32·0) In view of largely equivalent clinical cure across all and 11·4% (−1·2 to 23·7) respectively. Although clinical timepoints and low microbiological recurrence rates cure rates were similar across all treatment arms, that were on par between the groups at follow-up, plus cefepime–nacubactam showed a particularly strong the fact that the potential importance of these novel advantage in microbiological eradication, suggesting β-lactam and β-lactamase inhibitor combinations as improved pathogen clearance at test-of-cure. These antibiotics for carbapenem-resistant Gram-negative findings highlight the potential value of nacubactam- pathogens remains unknown, we believe that there are based combinations, particularly in infections caused by two options for antibiotic stewardship: first, cefepime– resistant Gram-negative bacteria. nacubactam and aztreonam–nacubactam could be used Notably, efficacy was also observed among patients for the treatment of ESBL-producing Enterobacterales as with infections caused by ESBL-producing pathogens carbapenem-sparing regimens; or second, these novel and among those with secondary bacteraemia, β-lactam and β-lactamase inhibitor combinations could 1894 Comment be reserved for infections caused by Enterobacterales pricing of these new β-lactam and β-lactamase inhibitor resistant to all other antibiotic options. combinations, challenging equitable access for all At some point in our history, we need to hold back who could benefit. We anticipate that the producers of on the global use of an antibiotic (or antibiotics) that cefepime–nacubactam and aztreonam–nacubactam will could have an important role in the treatment of have equity of access firmly in their sights. infections caused by the most resistant bacteria, rather In summary, cefepime–nacubactam and potentially than applying increased selection pressure on bacteria aztreonam–nacubactam are destined to join the by using it for infections for which there are current expanding group of novel β-lactam and β-lactamase antibiotics with good efficacy. We believe that this inhibitor combinations of antibiotics for use in time has come, and that cefepime–nacubactam and treating increasingly resistant Enterobacterales-caused aztreonam–nacubactam should be stewarded such that infections. Exactly how they should be positioned to they are not used as carbapenem-sparing regimens. optimise management and ensure maximum longevity, Once the results of the ongoing phase 3 Integral-2 remains to be determined. study (NCT05905055) are available, we will be able to We declare no competing interests re-assess the optimal positioning of these antibiotics *Marc Mendelson, Adrian Brink in the management of resistant Gram-negative marc.mendelson@uct.ac.za Enterobacterale-caused infections. Division of Infectious Diseases and HIV Medicine, Department of Medicine (MM) Despite the promising findings, several limitations and National Health Laboratory Service (AB), Groote Schuur Hospital, University of Cape Town, Cape Town 7935, South Africa; Division of Medical Microbiology, should be considered. The exclusion of carbapenem- Department of Pathology (AB) and Institute of Infectious Disease and Molecular resistant pathogens limits direct conclusions about Medicine (AB), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa efficacy in this particularly challenging population. In  Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract addition, most study participants were recruited from infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol 2015; 13: 269–84. eastern Europe, which might influence generalisability 2 Tamma PD, Aitken SL, Bonomo RA, et al. Infectious Diseases Society of to regions with different resistance epidemiology. America guidance on treatment of antimicrobial-resistant Gram-negative infections. Clin Infect Dis 2022; 74: 2116–27. This geographical focus in eastern Europe, China, 3 Papp-Wallace KM, Bonomo RA. New β-lactamase inhibitors in the clinic. and Japan yielded cohorts containing only White Infect Dis Clin North Am 2019; 33: 1065–86. 4 Takahashi S, Tateda K, Yanagihara K, et al. Efficacy and safety of cefepime– or Asian participants. Although pharmacokinetic nacubactam and aztreonam–nacubactam compared with imipenem– studies of nacubactam-containing antibiotics have cilastatin for complicated urinary tract infection or acute uncomplicated pyelonephritis (Integral-1): a double-blind, randomised phase 3 trial. Lancet shown similarity between these two racial groups, the 2026; 407: 1929–40. 5 Mushtaq S, Vickers A, Doumith M, Livermore DM, Woodford N. Activity of absence of other races in this study leaves a gap in our nacubactam combinations against β-lactamase-producing understanding of the efficacy of these two β-lactam and Enterobacterales. J Antimicrob Chemother 2019; 74: 953–60. 6 Mallalieu NL, Winter E, Fettner S, et al. Safety, tolerability, and β-lactamase inhibitor combinations across different pharmacokinetics of nacubactam alone and with meropenem. racial groups. The trial design did not include an oral Antimicrob Agents Chemother 2020; 64: e02229–19. 7 Rodriguez-Baño J, Gutiérrez-Guitiérrez B, Machuca I, Pascual A. Treatment step-down strategy, a common practice in real-world of infections caused by extended-spectrum β-lactamase-, AmpC-, and Carbapenemase-producing Enterobacteriaceae. Clin Microbiol Rev 2018; management of urinary tract infections.¹ As with 31: e00079–17 almost all new antibiotics, a limitation is likely to be the Vaccine impact in Gavi-supported countries: balancing evidence with policy needs Vaccines remain one of the most impactful and cost- up of immunisation programmes.1 As the incidence of See Articles page 1941 effective public health interventions. Decades of evidence previously debilitating vaccine-preventable childhood from randomised controlled trials and epidemiological diseases diminishes due to vaccination efforts, the studies have shown the impact of vaccines on perceived importance of immunisation could become less population health following the introduction and scale- evident to the public. Amid rising vaccine hesitancy and --- [PDF原文](https://sci-net.xyz/storage/7932541/d6247b54290b50af98d3da7c3202aa7fa2eec4c01019d77e00621220f66857cf/Emerging-lactam-and-lactamase-inhibitor-strategies-for-complicated-urinary-tract-infections.pdf) DOI: 10.1016/S0140-6736(26)00703-8