Efficacy and safety of cefepime-nacubactam and aztreonam-nacubactam compared

# Efficacy and safety of cefepime–nacubactam and aztreonam–nacubactam compared with imipenem–cilastatin for complicated urinary tract infection or acute uncomplicated pyelonephritis (Integral-1): a double-blind, randomised phase 3 trial *The Lancet 2026* Articles Efficacy and safety of cefepime–nacubactam and aztreonam–nacubactam compared with imipenem– cilastatin for complicated urinary tract infection or acute uncomplicated pyelonephritis (Integral-1): a double-blind, randomised phase 3 trial Satoshi Takahashi, Kazuhiro Tateda, Katsunori Yanagihara, Haihui Huang, Yohei Doi, Mitsuru Yasuda, Kazuaki Matsumoto, Masayo Sumiya, Risako Takaya, Keisuke Suwada, Satoshi Kamiyabu, Yuji Sasagawa, Takeshi Minamida, Seiji Kato, Kenichiro Kondo, Takeshi Naruse, Hiroshige Mikamo Summary Background Nacubactam (OP0595) is a newly developed diazabicyclooctane β-lactamase inhibitor used in combination Lancet 2026; 407: 1929–40 with cefepime or aztreonam. We assessed the ecacy and safety of cefepime–nacubactam and aztreonam–nacubactam See Comment page 1893 versus imipenem–cilastatin in complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis. For the plain language summary see Online for Methods The Integral-1 global, phase 3, multicentre, randomised, double-blind study recruited adults (aged ≥18 years) appendix 1 with cUTI or acute uncomplicated pyelonephritis at 79 sites in Bulgaria, China, Czech Republic, Estonia, Georgia, Department of Infection Control and Laboratory Japan, Latvia, Lithuania, and Slovakia. Patients were randomly assigned (2:1:1) to receive intravenous cefepime (2 g) Medicine, Sapporo Medical plus nacubactam (1 g), aztreonam (2 g) plus nacubactam (1 g), or imipenem (1 g) plus cilastatin (1 g) every 8 h for University School of Medicine, 5–14 days. Randomisation was stratified by diagnosis and geographical region. The primary endpoint was the Sapporo, Japan (S Takahashi MD, proportion of patients achieving composite clinical and microbiological success at test of cure in the microbiological M Yasuda MD); Department of Microbiology and Infectious modified intention-to-treat population—all patients who were randomly assigned, received any amount of the study Diseases, Toho University drug, and had a baseline qualifying pathogen that was susceptible to imipenem and meropenem. The prespecified School of Medicine, Tokyo, non-inferiority margin was more than 15 percentage points dierence; the superiority margin was more than zero Japan (K Tateda MD); percentage points dierence, for the lower bound of the two-sided 95% CI for imipenem–cilastatin. Safety was Department of Laboratory Medicine, Nagasaki University assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, Hospital, Nagasaki, Japan NCT05887908. (K Yanagihara MD); Institute of Antibiotics, Huashan Hospital, Findings Between May 22, 2023, and Nov 26, 2024, 614 patients were randomly assigned and 431 were included in the Fudan University, Shanghai, China (H Huang MD); primary ecacy analysis (cefepime–nacubactam [n=214], aztreonam–nacubactam [n=112], or imipenem–cilastatin Departments of Microbiology [n=105]); 228 patients (53%) were male and 203 (47%) were female. The primary endpoint was achieved by 176 (82%) of and Infectious Diseases, Fujita 214, 81 (72%) of 112, and 64 (61%) of 105 patients in the cefepime–nacubactam, aztreonam–nacubactam, and imipenem– Health University School of cilastatin groups, respectively. The percentage dierence in the success rate versus imipenem–cilastatin was 21·3% Medicine, Toyoake, Japan (Y Doi MD); Division of (95% CI 10·9 to 32·0) for cefepime–nacubactam (non-inferior and superior), and 11·4% (−1·2 to 23·7) for aztreonam– Infectious Diseases, University nacubactam (non-inferior). Treatment-emergent adverse events were reported in 100 (33%) of 306, 45 (30%) of 152, and of Pittsburgh School of 65 (43%) of 150 patients in the cefepime–nacubactam, aztreonam–nacubactam, and imipenem–cilastatin groups, Medicine, Pittsburgh, PA, USA respectively. No treatment-related deaths occurred. (Y Doi); Division of Pharmacodynamics, Keio University Faculty of Interpretation Cefepime–nacubactam and aztreonam–nacubactam are potential treatment options for Gram-negative Pharmacy, Tokyo, Japan cUTI and acute uncomplicated pyelonephritis, including infections caused by antimicrobial-resistant strains. (K Matsumoto PhD); Meiji Seika Pharma, Tokyo, Japan (M Sumiya MSc, R Takaya MPH, Funding Meiji Seika Pharma and Japan Agency for Medical Research and Development. K Suwada BSc, S Kamiyabu MSc, Y Sasagawa BSc, Copyright © 2026 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, T Minamida BSc, S Kato MSc, and similar technologies. K Kondo PhD, T Naruse MSc); Department of Clinical Infectious Diseases, Aichi Introduction failure, wider spectrum of aetiological bacteria, and a much Medical University Hospital, Urinary tract infection (UTI) is a major cause of higher risk of clinical complications compared with Nagakute, Japan (H Mikamo MD) hospitalisation and is associated with substantial uncomplicated UTIs.4 UTIs, including cUTIs, are most morbidity and mortality and a high economic burden.1,2 commonly caused by Escherichia coli and Klebsiella species, Complicated UTIs (cUTIs) occur in association with a although a wide variety of organisms can cause cUTIs.4 structural or functional abnormality of the genitourinary Infections with carbapenem-resistant Enterobacterales and tract3 and are associated with a higher risk of treatment third-generation cephalosporin-resistant Enterob acterales Articles Correspondence to: Research in context Dr Hiroshige Mikamo, Department of Clinical Infectious Evidence before this study of cefepime–nacubactam and aztreonam–nacubactam, which Diseases, Aichi Medical University Hospital, Nagakute, To design this study, we searched the Food and Drug was supported by the non-inferiority of cefepime–nacubactam Aichi 480–1195, Japan Administration, European Medicines Agency (EMA), and and aztreonam–nacubactam versus imipenem–cilastatin and mikamo@aichi-med-u.ac.jp Pharmaceuticals and Medical Devices Agency (PMDA) the superiority of cefepime–nacubactam versus imipenem– guidelines for information related to conducting clinical trials of cilastatin in patients with cUTI or acute uncomplicated complicated urinary tract infections (cUTI). PubMed was also pyelonephritis caused by Gram-negative bacteria except searched for randomised controlled trials intended to support a Acinetobacter species, including antimicrobial-resistant strains. marketing application for new antibacterial drugs to treat Cefepime–nacubactam and aztreonam–nacubactam were carbapenem-resistant infections that were published between shown to have acceptable safety profiles. A separate pathogen- July 10, 2019, and July 17, 2020, using the terms “complicated directed study in patients with carbapenem-resistant infections urinary tract infections”, “phase 2”, and “phase 3”. We also had will provide additional valuable information about cefepime– consultations with the EMA and PMDA regarding the nacubactam and aztreonam–nacubactam. appropriate study population and acceptable non-inferiority Implications of all the available evidence margins. To our knowledge, there have been no substantial Integral-1 showed that cefepime–nacubactam and aztreonam– updates in the evidence regarding trial design guidelines for nacubactam are effective and well tolerated for the treatment cUTI or acute uncomplicated pyelonephritis or for similar drug of cUTI or acute uncomplicated pyelonephritis and related trial designs since 2020. secondary bacteraemia caused by Gram-negative bacteria Nacubactam exhibits potent in-vitro activity against a large except Acinetobacter species, including antimicrobial-resistant group of Enterobacterales when combined with cefepime or strains. It was necessary to exclude patients with carbapenem- aztreonam, including New Delhi metallo-β-lactamase-producing resistant pathogens, given that imipenem, a carbapenem, was isolates. Human simulated doses of cefepime–nacubactam and used as the active comparator. Adding the results of this study aztreonam–nacubactam show potent in-vivo efficacy in mouse to those of the existing pharmacokinetic and non-clinical thigh and lung infection models. The safety and tolerability of pharmacology studies strengthens the evidence that supports cefepime–nacubactam and aztreonam–nacubactam in healthy cefepime–nacubactam and aztreonam–nacubactam as adults have been confirmed in phase 1 trials. important new treatments for antimicrobial-resistant Gram- negative bacterial infections. A clinical trial to assess efficacy of Added value of this study cefepime–nacubactam and aztreonam–nacubactam for To our knowledge, Integral-1 is the first study to evaluate the infections caused by carbapenem-resistant Enterobacterales efficacy and safety of cefepime–nacubactam and (Integral-2) is ongoing. aztreonam–nacubactam in patients with cUTI or acute uncomplicated pyelonephritis. This study showed the efficacy are dicult to treat because of their resistance to multiple β-lactamases (class A and class C and some in class D), antibacterial agents. Both are listed as critical groups on the resulting in the protection of the partner β-lactam; and WHO Bacterial Priority Pathogens list, representing (2) inhibiting penicillin-binding protein 2 of serious threats to public health.5 Infections caused by Enterobacterales, resulting in antibacterial activity and extended-spectrum β-lactamase (ESBL)-producing bacteria enhanced activity of β-lactam agents.10 Two types of are also dicult to treat because of their resistance to third- combinations (cefepime–nacubactam and aztreonam– generation cephalosporins, often requiring treatment with nacubactam) have been developed to adapt to regional a carbapenem.6 A growing diversity of β-lactamases dierences in the epidemiology of resistant pathogens. produced by Gram-negative bacteria poses a challenge to Two phase 3 clinical studies have been initiated to current antibacterial treatment. To help combat such further evaluate the clinical use of nacubactam: pathogens and prevent the emergence of carbapenem- Integral-1 (NCT05887908), the results of which are resistant strains, alternative antibacterials are needed to reported here, and Integral-2, an ongoing phase 3 study support carbapenem-sparing treatment strategies.3,7–9 The assessing the ecacy and safety of cefepime–nacubactam development of new, highly eective β-lactamase inhibitors and aztreonam–nacubactam compared with the best could contribute to this. available therapy for adults with various infections, Nacubactam (OP0595) is a recently developed including cUTI and acute uncomplicated pyelone- diazabicyclooctane β-lactamase inhibitor with potent phritis, caused by carbapenem-resistant Enterobacterales activity against carbapenem-resistant Enterobacterales (NCT05905055). The Integral-1 study aimed to compare and third-generation cephalosporin-resistant the ecacy and safety of cefepime–nacubactam and Enterobacterales, including ESBL producers, when aztreonam–nacubactam versus imipenem–cilastatin in combined with cefepime or aztreonam.10 Nacubactam patients with cUTI or acute uncomplicated has a dual mode of action: (1) inhibiting serine pyelonephritis. 1930 Articles Methods investigator received the results of the baseline urine Study design culture, in cases where all other entry criteria were Integral-1 is a phase 3, multicentre, randomised, double- fulfilled. If a patient’s baseline urine culture was negative blind study. The study was conducted at 79 sites in after randomisation, the study investigator decided Bulgaria, China, Czech Republic, Estonia, Georgia, whether the patient should continue to receive the study Japan, Latvia, Lithuania, and Slovakia between drug or discontinue the study drug and initiate non-study May 22, 2023, and Nov 26, 2024. A list of principal antibiotics. Sex data were self-reported by the trial investigators and study sites is available in appendix 2 participants, with male, female, undierentiated, and See Online for appendix 2 (pp 2–5). The protocol was approved by each site’s unknown listed as options. All patients provided written institutional review board or independent ethics informed consent. committee and is available in appendix 2, along with the statistical analysis plan. The study was conducted in Randomisation and masking accordance with the Declaration of Helsinki, the Study investigators enrolled patients at each site. Patients International Conference on Harmonisation guidelines were screened and randomly allocated in a 2:1:1 ratio to for Good Clinical Practice, and applicable laws and receive cefepime–nacubactam, aztreonam–nacubactam, regulations. No patients were involved in setting the or imipenem–cilastatin using a centralised interactive research questions or the outcome measures, nor were response technology system. The treatment assignment they involved in developing plans for recruitment, number and information on assigned treatment group design, or implementation of the study. No patients were were sent to the unmasked pharmacist, or qualified asked to advise on interpretation or writing up of results. unmasked designee, who prepared the intravenous study drug at each study site, and a masked randomisation Patients notification was sent to masked study site personnel. To Adult patients (aged ≥18 years) were eligible to participate ensure balance among treatment groups, randomisation in the study if they weighed 140 kg or less, had a diagnosis was stratified by diagnosis (cUTI or acute uncomplicated of cUTI or acute uncomplicated pyelonephritis as defined pyelonephritis) and by geographical region (Japan, China, in appendix 2 (p 6) and an expected intravenous or other). Enrolment was set so that at least 30% of antibacterial treatment duration of at least 5 days for patients had a diagnosis of acute uncomplicated cUTI or acute uncomplicated pyelonephritis, and a pyelonephritis and at least 60% had a diagnosis of cUTI. known or suspected baseline positive urine culture The study investigator, site personnel, sponsor, and specimen (≥10⁵ colony-forming units [CFU]/mL of an sponsor’s designees involved in monitoring, data uncontaminated, Gram-negative uropathogen sus- management, or other aspects of the study were unaware ceptible to meropenem and imipenem) obtained within of the treatment assignment. The site pharmacist, or 48 h before the first dose of the study drug. Patients with qualified designee, who prepared the intravenous study secondary bacteraemia, which was defined as presence of drug was unmasked. The infusion bag containing the an organism or organisms isolated from a non- study drug was labelled with the patient’s identification contaminated blood culture containing the same number but did not identify the study drug; an amber organism or organisms isolated from a urine culture, intravenous bag was placed over the infusion bag to were included in the study, categorised by the primary maintain masking. indication (cUTI or acute uncomplicated pyelonephritis) and recorded as having secondary bacteraemia. The key Procedures exclusion criteria were a known imipenem-resistant, Patients were required to be hospitalised at the start of or meropenem-resistant, or both, Gram-negative the study and the study drug was administered every 8 h uropathogen (≥10⁵ CFU/mL); detection of only a known (range 7–9 h) by intravenous infusion over a period of Gram-positive uropathogen (≥10⁵ CFU/mL); a contam- 60 min (range 45–75 min). Patients with a CrCl rate of inated culture (≥3 bacterial organisms ≥10⁵ CFU/mL 30 mL/min or greater and less than 60 mL/min received isolated from the study-qualifying urine culture); known 1 g cefepime plus 0·5 g nacubactam, 1 g aztreonam plus or suspected single or concurrent infection with 0·5 g nacubactam, or 0·5 g imipenem plus 0·5 g cilastatin, Acinetobacter species or other organisms not adequately every 8 h. Patients with a CrCl rate of 60 mL/min covered by the study drug; a complete obstruction of the or greater and less than 90 mL/min received 2 g cefepime urinary tract; receipt of a potentially eective systemic plus 1 g nacubactam, 2 g aztreonam plus 1 g nacubactam, antibacterial therapy within 48 h before the first dose of or 0·75 g imipenem plus 0·75 g cilastatin, every 8 h. study drug (with the exception that no more than 15% of Patients with a CrCl rate of 90 mL/min or greater and patients could have received a single dose of a short- 240 mL/min or less received 2 g cefepime plus 1 g acting antibacterial agent); or an estimated creatinine nacubactam, 2 g aztreonam plus 1 g nacubactam, or 1 g clearance (CrCl) rate of less than 30 mL/min or more imipenem plus 1 g cilastatin, every 8 h. All patients were than 240 mL/min. Patients could be enrolled and start treated for a minimum of 5–10 days and up to 14 days if intravenous study drug therapy before the study needed. Oral step-down therapy was not permitted. Articles End of treatment assessments were performed on the of cure and the microbiological outcome of eradication, day of the last study drug dose or within 24 h following which were assessed centrally. The clinical outcomes the day of the last study drug dose. Patients attended were assessed by the investigators at each study site, and two follow-up visits, which included a test of cure visit the microbiological outcomes were assessed based on 7 days (range 5–9) after the end of treatment visit and a both test results obtained from each study site and those follow-up visit 14 days (range 12–16) after the end of obtained from the central laboratory. Full details of the treatment. At the end of treatment, test of cure, and clinical and microbiological outcome criteria are available follow-up visits, patients were assessed for clinical in appendix 2 (p 7). outcome and a urine sample was collected for culture. The secondary endpoints included the proportion of patients with composite clinical and microbiological Study endpoints outcome of success, clinical outcome of cure, and The primary endpoint was the proportion of patients microbiological outcome of eradication at the end of who achieved composite clinical and microbiological treatment and follow-up visits in the microbiological success at the test of cure visit in the mITT, and at the test of cure visit in patients with micro biological modified intention-to-treat (mITT) secondary bacteraemia at baseline and patients with population. Composite clinical and microbiological confirmed ESBL-positive status in the microbiological success were defined as the composite clinical outcome mITT. 678 patients assessed for eligibility 64 ineligible 614 enrolled 614 randomly assigned 309 assigned to cefepime–nacubactam 154 assigned to aztreonam–nacubactam 151 assigned to imipenem–cilastatin 2 did not receive study drug 1 did not receive study drug 1 ICH-GCP deviation (assigned twice) 1 ineligible (assigned in error) 307 included in the ITT analysis 154 included in the ITT analysis 150 included in the ITT analysis 1 excluded (did not receive study 2 excluded (did not receive study drug) drug) 306 included in the mITT, safety analyses 152 included in the mITT, safety analyses 150 included in the mITT, safety analyses 92 excluded 40 excluded 45 excluded 60 no baseline qualifying 25 no baseline qualifying 26 no baseline qualifying pathogen pathogen pathogen 32 baseline qualifying pathogen 15 baseline qualifying pathogen 19 baseline qualifying pathogen not susceptible to imipenem not susceptible to imipenem not susceptible to imipenem or meropenem or meropenem or meropenem 214 included in the microbiological mITT 112 included in the microbiological mITT 105 included in the microbiological mITT Figure: Trial profile The ITT population was defined as all patients who were randomly allocated to treatment. The mITT and safety populations were defined as all patients who met the ITT criteria and received any amount of the study drug. The microbiological mITT population was defined as all patients who met the mITT criteria and had a baseline qualifying pathogen that was susceptible to imipenem and meropenem. ICH-GCP=International Council for Harmonisation–Good Clinical Practice. ITT=intention-to- treat. mITT=modified ITT. 1932 Articles Adverse events, treatment-emergent adverse events, treatment success at the test of cure visit in the and adverse drug reactions were monitored for safety. microbiological mITT population was more than zero, The study investigator assessed the severity of adverse superiority was declared. Furthermore, if non-inferiority events and adverse drug reactions and determined the of the cefepime–nacubactam group was declared for the potential relationship of adverse events to the study drug. primary ecacy endpoint, the non-inferiority hypothesis Adverse events and adverse drug reactions were coded by test for the aztreonam–nacubactam group was performed System Organ Class and Preferred Term according to the using a hierarchical gatekeeping approach for overall Medical Dictionary for Regulatory Activities (MedDRA) control of the type I error. For this analysis, and for the version 26.0. dierence (aztreonam–nacubactam group minus imipenem–cilastatin group) in treatment success at the Statistical analysis test of cure visit, the same approach as in the cefepime– Using a 15% non-inferiority margin, a one-sided nacubactam group was used. α of 0·025, 80% power, a composite clinical and Patients with missing data or who were lost to follow-up microbiological success rate of 70% in each at the test of cure visit were defined as treatment failure treatment group (cefepime–nacubactam, imipenem– cilastatin) at the test of cure visit, and a 2:1 allocation ratio, Cefepime– Aztreonam– Imipenem– Total a total of 330 patients were required in the microbiological nacubactam nacubactam cilastatin (n=431) mITT population. Additionally, 110 patients were required (n=214) (n=112) (n=105) in the microbiological mITT population for the Age, years 63·62 (14·83) 66·41 (14·04) 65·46 (15·57) 64·79 (14·83) aztreonam–nacubactam group in order to evaluate the Sex ecacy and safety of aztreonam–nacubactam with the Male 111 (52%) 61 (54%) 56 (53%) 228 (53%) same precision as the imipenem–cilastatin group. Female 103 (48%) 51 (46%) 49 (47%) 203 (47%) Assuming 75% of patients were evaluable in the Race microbiological mITT population, it was determined that Asian (Japanese) 12 (6%) 6 (5%) 5 (5%) 23 (5%) approximately 600 patients (using a 2:1:1 allocation ratio Asian (Chinese) 23 (11%) 9 (8%) 7 (7%) 39 (9%) with 300 patients in the cefepime–nacubactam group and Asian (other) 0 1 (<1%) 0 1 (<1%) 150 patients each in the aztreonam–nacubactam and White 179 (84%) 96 (86%) 93 (89%) 368 (85%) imipenem–cilastatin groups) were needed to conduct the Geographical region study. Japan 12 (6%) 6 (5%) 5 (5%) 23 (5%) The microbiological mITT population included all China 23 (11%) 10 (9%) 7 (7%) 40 (9%) patients who were randomly assigned, received any Other* 179 (84%) 96 (86%) 93 (89%) 368 (85%) amount of the study drug, and had a baseline qualifying Weight, kg 79·11 (17·75) 81·26 (19·20) 77·47 (17·48) 79·27 (18·08) pathogen that was susceptible to imipenem and Body mass index, kg/m² 27·52 (5·42) 28·49 (5·37) 26·94 (5·59) 27·62 (5·46) meropenem. The safety population included all patients Primary infection type who received at least one dose of the study drug. Complicated urinary tract infection 137 (64%) 76 (68%) 73 (70%) 286 (66%) Summary statistics were used to describe continuous Acute uncomplicated pyelonephritis 77 (36%) 36 (32%) 32 (30%) 145 (34%) variables; frequency and percentage were used to Creatinine clearance, mL/min describe categorical variables. For the primary and secondary endpoints, the Miettinen Total 86·9 (34·9; 87·8 (40·1) 82·0 (32·4; 85·9 (35·8; n=212) n=104) n=428) and Nurminen method11 was used to calculate the <30 1 (<1%) 3 (3%) 0 4 (1%) 95% CIs for the observed dierence in the proportion of 30 to <60 46 (21%) 30 (27%) 27 (26%) 103 (24%) patients in each group. The prespecified non-inferiority 60 to <90 77 (36%) 30 (27%) 44 (42%) 151 (35%) and superiority margins were defined as more than 90 to <240 88 (41%) 49 (44%) 33 (31%) 170 (39%) 15 percentage points difference and more than zero Secondary bacteraemia 15 (7%) 9 (8%) 10 (10%) 34 (8%) percentage points dierence, respectively, for the lower Prior short-acting antibacterial therapy 18 (8%) 12 (11%) 12 (11%) 42 (10%) bound of the two-sided 95% CI for imipenem–cilastatin. Resistance type Specifically, if the lower limit of the two-sided 95% CI for ESBL-positive 48 (22%) 34 (30%) 27 (26%) 109 (25%) the dierence between treatment groups at the test of cure visit in the microbiological mITT population was Escherichia coli 34 (16%) 25 (22%) 21 (20%) 80 (19%) more than 15 percentage points difference for the primary Klebsiella pneumoniae 15 (7%) 8 (7%) 6 (6%) 29 (7%) analysis, the null hypothesis was rejected and non- Proteus mirabilis 0 1 (<1%) 0 1 (<1%) inferiority was concluded based on the primary ecacy Data are n (%) or mean (SD). mITT=modified intention-to-treat. ESBL=extended-spectrum β-lactamases. *Includes endpoint. If non-inferiority was declared for the primary Bulgaria, Czech Republic, Estonia, Georgia, Latvia, Lithuania, and Slovakia. ESBL defined as testing with a ceftazidime broth microdilution minimum inhibitory concentration of 2 μg/mL or greater, and a 5 mm or greater increase in zone ecacy endpoint, a test for superiority was performed size when tested with ceftazidime-clavulanate or cefotaxime-clavulanate disks, compared with the zone size for discs using a hierarchical gatekeeping approach for overall containing the agent alone. control of the type I error. For this analysis, if the lower Table 1: Patient demographics and background characteristics (microbiological mITT population) bound of the 95% CI for the treatment dierence in Articles (clinical outcome of failure for the last visit before the Results test of cure visit) or treatment indeterminate (any clinical Between May 22, 2023, and Nov 26, 2024, 614 patients outcome except failure for the last visit before the test of were randomly assigned to receive cefepime–nacubactam cure visit) for the primary endpoint; patients defined as (n=309), aztreonam–nacubactam (n=154), or imipenem– failure or indeterminate were included only in the cilastatin (n=151; figure). Of the 309 patients assigned to denominator of the success rate calculation. the cefepime–nacubactam group, 306 received the study SAS version 9.4 was used to perform the statistical treatment and were included in the safety population analysis. (three patients were excluded: deviation from An independent Data Safety Monitoring Board International Council for Harmonisation—Good Clinical reviewed accumulated safety data and serious adverse Practice, n=1; ineligible patient randomised in error, n=1; events on an ongoing basis and made recommendations and did not receive study drug, n=1), and 214 were based on the safety data. The study was registered included in the microbiological mITT (92 patients were with ClinicalTrials.gov (https://clinicaltrials.gov/study/ excluded: no baseline qualifying pathogen, n=60; NCT05887908). baseline qualifying pathogen not susceptible to imipenem or meropenem, n=32). Of the 154 patients Role of the funding source assigned to the aztreonam–nacubactam group, Meiji Seika Pharma had a role in the study design, data 152 received the study treatment and were included in collection, data analysis, data interpretation, writing of the safety population (two patients were excluded: neither the report, and decision to submit the paper for received the study drug) and 112 were included in the publication. The Japan Agency for Medical Research and microbiological mITT population (40 patients were Development had no role in in the study design, data excluded: no baseline qualifying pathogen, n=25; collection, data analysis, data interpretation, writing of baseline qualifying pathogen not susceptible to the report, and decision to submit the paper for imipenem or meropenem, n=15). Of the 151 patients publication. assigned to the imipenem–cilastatin group, 150 received the study treatment and were included in the safety analysis (one patient did not receive the study drug) and Cefepime– Aztreonam– Imipenem– Total nacubactam nacubactam cilastatin (n=431) 105 were included in the microbiological mITT (n=214) (n=112) (n=105) population (45 patients were excluded: no baseline Baseline pathogen qualifying pathogen, n=26; baseline qualifying pathogen Escherichia coli 162 (76%) 89 (80%) 76 (72%) 327 (76%) not susceptible to imipenem or meropenem, n=19). Klebsiella pneumoniae 32 (15%) 12 (11%) 16 (15%) 60 (14%) For the overall microbiological mITT population Proteus mirabilis 2 (1%) 7 (6%) 2 (2%) 11 (3%) (n=431), the age, BMI, and CrCl mean rates at baseline Klebsiella oxytoca 5 (2%) 2 (2%) 1 (1%) 8 (2%) were 64·79 years (SD 14·83), 27·62 kg/m² (5·46), and Pseudomonas aeruginosa 5 (2%) 1 (1%) 2 (2%) 8 (2%) 85·9 mL/min (35·8; n=428); 228 (53%) patients were male and 203 (47%) were female, 368 (85%) were White, Enterobacter hormaechei 4 (2%) 1 (1%) 2 (2%) 7 (2%) 39 (9%) were Chinese, and 23 (5%) were Japanese. Citrobacter freundii 2 (1%) 1 (1%) 1 (1%) 4 (1%) Overall of 431 patients, 286 (66%) were diagnosed with Klebsiella variicola 2 (1%) 1 (1%) 1 (1%) 4 (1%) cUTI and 145 (34%) were diagnosed with acute Providencia rettgeri 1 (<1%) 0 2 (2%) 3 (1%) uncomplicated pyelonephritis; 34 (8%) had secondary Citrobacter koseri 1 (<1%) 0 1 (1%) 2 (<1%) bacteraemia. ESBL-positive pathogens were identified in Klebsiella aerogenes 1 (<1%) 1 (1%) 0 2 (<1%) 109 (25%) of 431 patients. The baseline characteristics Proteus hauseri 2 (1%) 0 0 2 (<1%) and key microbiological features were well balanced Acinetobacter junii 0 1 (1%) 0 1 (<1%) among the treatment groups (table 1). Citrobacter spp 0 0 1 (1%) 1 (<1%) Baseline pathogens were similarly distributed among Enterobacter spp 0 0 1 (1%) 1 (<1%) the treatment groups (table 2. In the overall Enterobacter bugandensis 1 (<1%) 0 0 1 (<1%) microbiological mITT population, the most common Raoultella ornithinolytica 1 (<1%) 0 0 1 (<1%) pathogen was E coli (327 [76%] of 431), followed by Serratia marcescens 1 (<1%) 0 0 1 (<1%) K pneumoniae (60 [14%] of 431). All other pathogens Polymicrobial infection 8 (4%) 4 (4%) 1 (1%) 13 (3%) occurred at a frequency of less than 5%. Polymicrobial Escherichia coli and Klebsiella pneumoniae 4 (2%) 0 0 4 (1%) infection was present in 13 (3%) of 431 patients. Escherichia coli and Pseudomonas aeruginosa 2 (1%) 1 (1%) 0 3 (1%) In total, 176 (82%) of 214, 81 (72%) of 112, and Escherichia coli and Proteus mirabilis 1 (<1%) 1 (1%) 0 2 (<1%) 64 (61%) of 105 patients in the cefepime–nacubactam, Klebsiella oxytoca and Klebsiella pneumoniae 0 2 (2%) 0 2 (<1%) aztreonam–nacubactam, and imipenem–cilastatin Klebsiella pneumoniae and Providencia rettgeri 1 (<1%) 0 1 (1%) 2 (<1%) groups, respectively, achieved the primary endpoint of mITT=modified intention-to-treat. composite clinical outcome and microbiological success at the test of cure (table 3). The percentage dierence in Table 2: Summary of baseline pathogens (microbiological mITT population) the success rate versus the imipenem–cilastatin group 1934 Articles was 21·3% (95% CI 10·9 to 32·0) for the (95 of 105). At the follow-up visit, the success rates were cefepime–nacubactam group, meeting both the 69% (147 of 214), 65% (73 of 112), and 62% (65 of 105) for superiority and non-inferiority margins, and 11·4% the cefepime–nacubactam, aztreonam–nacubactam, and (−1·2 to 23·7) for the aztreonam–nacubactam group, imipenem–cilastatin groups, respectively (dierence: meeting the non-inferiority margin. The clinical cefepime–nacubactam vs imipenem–cilastatin, 6·8% outcome of cure was achieved for 195 (91%) of 214, 103 [95% CI −4·1 to 18·1]; aztreonam–nacubactam vs (92%) of 112, and 92 (88%) of 105 patients in the imipenem–cilastatin group, 3·3% [95% CI −9·5 to 16·0]; cefepime–nacubactam, aztreonam–nacubactam, and table 4). The respective cure rates were 88% (188 of 214), imipenem–cilastatin groups, respectively (table 3). The 88% (98 of 112), and 85% (89 of 105), and eradication rates percentage dierences in the cure rate for the cefepime– were 73% (157 of 214), 67% (75 of 112), and 65% (68 of 105). nacubactam and aztreonam–nacubactam groups versus The sensitivity analysis (adjusted for the randomisation the imipenem–cilastatin group were 3·5% (95% CI stratification factors of baseline entry diagnosis [cUTI or −3·3 to 11·8) and 4·3% (−3·9 to 13·0), respectively. The acute uncomplicated pyelonephritis] and geographical microbiological outcome of eradication was achieved for region [Japan, China, or other]) indicated consistent results 184 (86%) of 214, 83 (74%) of 112, and 67 (64%) of with the primary analysis (table 3) and confirmed the 105 patients in the cefepime–nacubactam, aztreonam– overall superiority of cefepime–nacubactam (176 [82%] of nacubactam, and imipenem–cilastatin groups, 214 patients) and non-inferiority of aztreonam–nacubactam respectively (table 3). The percentage dierences in the (81 [72%] of 112 patients) to imipenem–cilastatin (64 [61%] eradication rate for the cefepime–nacubactam and of 105 patients) for the composite clinical and aztreonam–nacubactam groups versus the imipenem– microbiological success at the test of cure visit with cilastatin group were 22·2% (12·2 to 32·7) and 10·3% treatment dierences of 21∙3% (95% CI 12·1 to 32·0) and (−2·0 to 22·5), respectively. Risk dierences according 11∙4% (95% CI −0·1 to 23·5), respectively (appendix 2 to sex, age, and diagnosis at baseline entry are shown in pp 9–10). appendix 2 (p 8). Among patients with secondary bacteraemia, success At the end of treatment, the success rates were 93% (199 rates for clinical cure and microbiological eradication for of 214), 91% (102 of 112), and 90% (94 of 105) for the secondary bacteraemia at the test of cure were 80% cefepime–nacubactam, aztreonam–nacubactam, and (12 of 15), 89% (eight of nine), and 60% (six of ten) for the imipenem–cilastatin groups, respectively (dierence: cefepime–nacubactam, aztreonam–nacubactam, and cefepime–nacubactam vs imipenem–cilastatin, 3·5% imipenem–cilastatin groups, respectively (treatment [95% CI −2·7 to 11·3]; aztreonam–nacubactam vs dierence: cefepime–nacubactam vs imipenem– imipenem–cilastatin group, 1·5% [95% CI −6·6 to 10·0]; cilastatin, 20·0% [95% CI −16·0 to 54·3]; table 4). The respective cure rates were 95% (204 of 214), aztreonam–nacubactam vs imipenem–cilastatin group, 95% (106 of 112), and 95% (100 of 105), and eradication 28·9% [−13·0 to 62·1]; appendix 2 pp 11–12). Also among rates were 95% (203 of 214), 94% (105 of 112), and 90% patients with secondary bacteraemia, 11 (73%) of 15, Cefepime–nacubactam Aztreonam–nacubactam Imipenem–cilastatin Treatment difference (95% CI) (n=214) (n=112) (n=105) Cefepime–nacubactam Aztreonam– vs imipenem–cilastatin nacubactam vs imipenem–cilastatin Composite clinical and microbiological success Success 176 (82·2% [76·5 to 87·1]) 81 (72·3% [63·1 to 80·4]) 64 (61·0% [50·9 to 70·3]) 21·3% (10·9 to 32·0) 11·4% (−1·2 to 23·7) Failure 26 (12%) 27 (24%) 34 (32%) ·· ·· Indeterminate 12 (6%) 4 (4%) 7 (7%) ·· ·· Clinical outcome Cure 195 (91·1% [86·5 to 94·6]) 103 (92·0% [85·3 to 96·3]) 92 (87·6% [79·8 to 93·2]) 3·5% (−3·3 to 11·8) 4·3% (−3·9 to 13·0) Failure 7 (3%) 3 (3%) 5 (5%) ·· ·· Indeterminate 12 (6%) 6 (5%) 8 (8%) ·· ·· Microbiological outcome Eradication 184 (86·0% [80·6 to 90·3]) 83 (74·1% [65·0 to 81·9]) 67 (63·8% [53·9 to 73·0]) 22·2% (12·2 to 32·7) 10·3% (−2·0 to 22·5) Persistence 0 0 0 ·· ·· Recurrence 14 (7%) 22 (20%) 28 (27%) ·· ·· Indeterminate 16 (7%) 7 (6%) 10 (10%) ·· ·· Data are n (% [95% CI]). mITT=modified intention-to-treat. Table 3: Clinical and microbiological success rates and outcomes at test of cure visit and between-group comparisons (mITT) Articles test of cure (treatment dierence: cefepime–nacubactam Cefepime– Aztreonam– Imipenem– Treatment difference (95% CI) vs imipenem–cilastatin 53·3% [95% CI 12·8 to 78·1]; nacubactam nacubactam cilastatin (n=214) (n=112) (n=105) aztreonam–nacubactam vs imipenem–cilastatin group, 24·4% [−18·4 to 60·5]). The respective cure rates Cefepime– Aztreonam– nacubactam nacubactam vs were 80% (12 of 15), 89% (eight of nine), and 50% vs imipenem– imipenem– (five of ten), and eradication rates were 73% (11 of 15), cilastatin cilastatin 44% (four of nine), and 30% (three of ten) in the End of treatment cefepime–nacubactam, aztreonam–nacubactam, and Composite clinical and microbiological success imipenem–cilastatin groups, respectively. Success 199 (93·0% 102 (91·1% 94 (89·5% 3·5% 1·5% Among patients with ESBL-producing bacterial [88·7 to 96·0]) [84·2 to 95·6]) [82·0 to 94·7]) (−2·7 to 11·3) (−6·6 to 10·0) infections, success rates were 75% (36 of 48), 68% Failure 10 (5%) 5 (4%) 7 (7%) ·· ·· (23 of 34), and 56% (15 of 27) at the test of cure for the Indeterminate 5 (2%) 5 (4%) 4 (4%) ·· ·· cefepime–nacubactam, aztreonam–nacubactam, and Clinical outcome imipenem–cilastatin groups, respectively (treatment Cure 204 (95·3% 106 (94·6% 100 (95·2% 0·1% −0·6% dierence: cefepime–nacubactam vs imipenem–cilastatin, [91·6 to 97·7]) [88·7 to 98·0]) [89·2 to 98·4]) (−4·6 to 6·4) (−7·1 to 6·0) 19·4% [95% CI −2·6 to 41·1]; aztreonam–nacubactam vs Failure 5 (2%) 1 (1%) 1 (1%) ·· ·· imipenem–cilastatin group, 12·1% [−12·3 to 35·7]; Indeterminate 5 (2%) 5 (4%) 4 (4%) ·· ·· appendix 2 pp 13–14). The respective cure rates were 85% Microbiological outcome (41 of 48), 91% (31 of 34), and 85% (23 of 27), and Eradication 203 (94·9% 105 (93·8% 95 (90·5% 4·4% 3·3% eradication rates were 81% (39 of 48), 68% (23 of 34), [91·0 to 97·4]) [87·5 to 97·5]) [83·2 to 95·3]) (−1·3 to 11·9) (−4·2 to 11·2) and 56% (15 of 27; appendix 2 pp 13–14). Persistence 0 0 0 ·· ·· In the cefepime–nacubactam, aztreonam–nacubactam, Recurrence 0 3 (3%) 1 (1%) ·· ·· and imipenem–cilastatin groups 102 (33%) of 306, Indeterminate 11 (5%) 4 (4%) 9 (9%) ·· ·· 47 (31%) of 152, and 66 (44%) of 150 patients experienced Follow-up any adverse event, respectively; six (2%) of 306, Composite clinical and microbiological success four (3%) of 152, and five (3%) of 150 patients experienced Success 147 (68·7% 73 (65·2% 65 (61·9% 6·8% 3·3% a serious adverse event; and one adverse event leading to [62·0 to 74·8]) [55·6 to 73·9]) [51·9 to 71·2]) (−4·1 to 18·1) (−9·5 to 16·0) death (lung cancer progression, not related to the study Failure 54 (25%) 34 (30%) 34 (32%) ·· ·· drug or intravenous procedure) was reported in the Indeterminate 13 (6%) 5 (4%) 6 (6%) ·· ·· cefepime–nacubactam group (table 5). In all three groups, Clinical outcome most treatment-emergent adverse events and adverse Cure 188 (87·9% 98 (87·5% 89 (84·8% 3·1% 2·7% drug reactions were mild or moderate in severity. [82·7 to 91·9]) [79·9 to 93·0]) [76·4 to 91·0]) (−4·5 to 12·1) (−6·6 to 12·3) Treatment-emergent adverse events leading to the Failure 7 (3%) 4 (4%) 2 (2%) ·· ·· discontinuation of the study drug occurred in Recurrence 6 (3%) 5 (4%) 7 (7%) ·· ·· seven (2%) of 306, two (1%) of 152, and Indeterminate 13 (6%) 5 (4%) 7 (7%) ·· ·· two (1%) of 150 patients in the cefepime–nacubactam, Microbiological outcome aztreonam–nacubactam, and imipenem–cilastatin Eradication* 157 (73·4% 75 (67·0% 68 (64·8% 8·6% 2·2% [66·9 to 79·2]) [57·4 to 75·6]) [54·8 to 73·8]) (−2·0 to 19·7) (−10·4 to 14·8) groups, respectively; and treatment-emergent adverse Presumed 56 (26%) 30 (27%) 18 (17%) ·· ·· events leading to study discontinuation occurred in eradication† seven (2%) of 306, two (1%) of 152, and Persistence 0 0 1 (1%) ·· ·· one (1%) of 150 patients (table 5). The most common Recurrence 40 (19%) 29 (26%) 25 (24%) ·· ·· treatment-emergent adverse events by MedDRA preferred Indeterminate 17 (8%) 8 (7%) 11 (10%) ·· ·· term were headache, which occurred most frequently in the aztreonam–nacubactam group (5% [eight of 152]), Data are n (% [95% CI). CFM= colony-forming units. mITT=modified intention-to-treat. *Includes presumed eradication. †Presumed eradication was assessed at follow-up and categorised as eradication only if the baseline followed by the imipenem–cilastatin group (4% [six of 150]) qualifying Gram-negative pathogen was eradicated (reduced to <10³ CFU/mL) at the test of cure visit, and a urine and the cefepime–nacubactam group (3% [ten of 306]); sample could not be collected but there was a clinical outcome of cure at follow-up; therefore, a urine sample should diarrhoea, which occurred most frequently in the also have been collected at follow-up, unless the baseline qualifying Gram-negative pathogen was eradicated (reduced to <10³ CFU/mL) at the treatment of cure visit. cefepime–nacubactam group (5% [14 of 306]), followed by the imipenem–cilastatin group (4% [six of 150]) and the Table 4: Clinical and microbiological success rates and outcomes at end of treatment visit and follow-up aztreonam–nacubactam group (2% [three of 152]); and visit and between-group comparisons (microbiological mITT population) nausea, which occurred most frequently in the imipenem–cilastatin group (7% [ten of 150]), followed by four (44%) of nine, and two (20%) of ten patients in the the cefepime–nacubactam group (2% [five of 306]) and cefepime–nacubactam, aztreonam–nacubactam, and the aztreonam–nacubactam group (1% [one of 152]; imipenem–cilastatin groups, respectively, achieved table 5). composite clinical outcome and microbiological success In the cefepime–nacubactam, aztreonam–nacubactam, from cUTI or acute uncomplicated pyelonephritis at the and imipenem–cilastatin groups, 44 (14%) of 306, 1936 Articles Cefepime–nacubactam Aztreonam– Imipenem–cilastatin Total (n=306) nacubactam (n=152) (n=150) (n=608) Any adverse event 102 (33% [208]) 47 (31% [105]) 66 (44% [135]) 215 (35% [448]) Any serious adverse event 6 (2% [7]) 4 (3% [4]) 5 (3% [7]) 15 (2% [18]) Any adverse event leading to death 1 (<1% [1]) 0 0 1 (<1% [1]) Any treatment-emergent adverse event 100 (33% [203]) 45 (30% [99]) 65 (43% [132]) 210 (35% [434]) Mild 67 (22%) 35 (23%) 42 (28%) 144 (24%) Moderate 28 (9%) 9 (6%) 20 (13%) 57 (9%) Severe 5 (2%) 1 (1%) 3 (2%) 9 (1%) Any adverse drug reaction 44 (14% [58]) 15 (10% [29]) 27 (18% [40]) 86 (14% [127]) Mild 35 (11%) 14 (9%) 19 (13%) 68 (11%) Moderate 8 (3%) 0 7 (5%) 15 (2%) Severe 1 (<1%) 1 (1%) 1 (1%) 3 (<1%) Any intravenous procedure-related treatment- 14 (5% [15]) 5 (3% [6]) 8 (5% [12]) 27 (4% [33]) emergent adverse event Any serious treatment-emergent adverse event 6 (2% [7]) 4 (3% [4]) 5 (3% [7]) 15 (2% [18]) Any treatment-emergent adverse event leading to 7 (2% [10]) 2 (1% [2]) 2 (1% [3]) 11 (2% [15]) discontinuation of study drug Any treatment-emergent adverse event leading to 7 (2% [7]) 2 (1% [2]) 1 (1% [2]) 10 (2% [11]) discontinuation of study Treatment-emergent adverse events by System Organ Class and MedDRA preferred term (experienced by ≥2% of patients in any treatment group) Gastrointestinal disorders 32 (10% [37]) 13 (9% [18]) 28 (19% [36]) 73 (12% [91]) Diarrhoea 14 (5% [14]) 3 (2% [3]) 6 (4% [6]) 23 (4% [23]) Nausea 5 (2% [5]) 1 (1% [1]) 10 (7% [10]) 16 (3% [16]) Constipation 6 (2% [6]) 3 (2% [3]) 4 (3% [6]) 13 (2% [15]) Vomiting 2 (<1% [2]) 1 (1% [1]) 5 (3% [5]) 8 (1% [8]) Abdominal pain upper 1 (<1% [1]) 1 (1% [1]) 3 (2% [3]) 5 (1% [5]) Infections and infestations 18 (6% [18]) 14 (9% [14]) 16 (11% [20]) 48 (8% [52]) Asymptomatic bacteriuria 3 (1% [3]) 7 (5% [7]) 5 (3% [5]) 15 (2% [15]) Nervous system disorders* 16 (5% [18]) 9 (6% [9]) 9 (6% [10]) 34 (6% [37]) Headache 10 (3% [11]) 8 (5% [8]) 6 (4% [6]) 24 (4% [25]) General disorder and administration site conditions 8 (3% [8]) 5 (3% [5]) 12 (8% [17]) 25 (4% [30]) Pyrexia 4 (1% [4]) 2 (1% [2]) 3 (2% [3]) 9 (1% [9]) Metabolism and nutrition disorders 11 (4% [17]) 4 (3% [4]) 4 (3% [8]) 19 (3% [31]) Hypokalaemia 6 (2% [6]) 1 (1% [1]) 2 (1% [2]) 9 (1% [9]) Skin and subcutaneous tissue disorders 8 (3% [8]) 4 (3% [4]) 4 (3% [4]) 16 (3% [16]) Rash 2 (<1% [2]) 2 (1% [2]) 4 (3% [4]) 8 (1% [8]) Vascular disorders 11 (4% [11]) 5 (3% [5]) 0 16 (3% [16]) Hypertension 5 (2% [5]) 3 (2% [3]) 0 8 (1% [8]) Data are n, participants (% [n, events]). Events are coded by System Organ Class and preferred term according to MedDRA version 26.0. MedDRA=Medical Dictionary for Regulatory Activities. *All nervous system disorders other than headache occurred at a frequency of less than 2%: cefepime–nacubactam, dizziness (three treatment- emergent adverse events in three patients [1%]), and cervical radiculopathy, dizziness postural, encephalopathy, and radiculopathy (one treatment-emergent adverse event in one patient [<1%] each); aztreonam–nacubactam, cerebral infarction (one treatment-emergent adverse event in one patient [<1%]); imipenem–cilastatin, neuralgia, paraesthesia, presyncope, and tremor (one treatment-emergent adverse event in one patient [<1%] each). Table 5: Overall summary of adverse events, treatment-emergent adverse events, adverse drug reactions, and breakdown of treatment-emergent adverse events occurring in minimum 2% of patients in any treatment group by System Organ Class and MedDRA preferred term (safety population) 15 (10%) of 152, and 27 (18%) of 150 patients experienced treatment of patients hospitalised with cUTI or acute any study drug-related treatment-emergent adverse uncomplicated pyelonephritis. The β-lactam plus event, respectively (appendix 2 pp 15–16). nacubactam combinations were eective in patients with secondary bacteraemia, and ecacy in patients with Discussion ESBL-producing bacterial infections was demonstrated Our results show the non-inferiority of cefepime– in both nacubactam groups. Cefepime–nacubactam and nacubactam and aztreonam–nacubactam versus aztreonam–nacubac tam were well tolerated and no new imipenem–cilastatin and the superiority of cefepime– safety concerns were identified. The choice of imipenem– nacubactam versus imipenem–cilastatin for the cilastatin as the comparator used in this study was based Articles on its demonstrated ecacy against Gram-negative cefepime–nacu bactam group (33% and 14%, respectively) pathogens isolated from patients with cUTI or acute and aztreonam–nacubactam group (30% and 10%, uncomplicated pyelonephritis. The drug combination is respectively) compared with the imipenem– widely used to treat cUTIs, and carbapenems are the cilastatin group (43% and 18%, respectively). The drug of choice against ESBL-producing Gram-negative incidences of study drug-related treatment-emergent patho gens, in particular for serious infections. adverse events observed for cefepime–nacubactam and Additionally, imipenem–cilastatin is available for the aztreonam–nacubactam were similar to those reported treatment of cUTI and acute uncomplicated for cefepime alone or aztreonam alone, based on their pyelonephritis in both Europe and the Asia–Pacific respective package inserts;20,21 therefore, our results region.12,13 Because baseline characteristics and suggest that nacubactam added to either drug does not microbiological features were well balanced between alter the safety profile. treatment groups overall and in the primary analysis This study has some limitations to consider. Patients population, the superiority of cefepime–nacubactam was with carbapenem-resistant infections were excluded not explained by dierences in these factors across from this study, as imipenem (a carbapenem class treatment groups. antibiotic) with cilastatin was used as the control Several antibacterials have been evaluated in clinical treatment. By excluding the oral step-down process in studies for treating cUTI and acute uncomplicated this trial, the eects of the study treatments could be pyelonephritis. These include cefepime–taniborbactam assessed without the potential confounding influence of (a β-lactam and β-lactamase inhibitor combination);14 additional antibacterial therapy. This strategy has also cefiderocol (a siderophore cephalosporin antibacterial);15 been adopted in previous similar studies.14,15 Nevertheless, a combination of relebactam (a β-lactamase inhibitor that we note that the absence of a step-down process to oral can restore imipenem activity against imipenem-non- medication and the need for inpatient participation in susceptible pathogens) with imipenem–cilastatin;16 and this study might not reflect the situation in real-world ceftazidime–avibactam.17 Avibactam is a β-lactamase clinical practice. To investigate ecacy and safety with inhibitor that restores the in-vitro activity of ceftazidime the same precision as in the imipenem–cilastatin group, against several β-lactamase-producing bacteria.18 the aztreonam–nacubactam group was assigned the Carbapenems have had inferior outcomes compared same target sample size as the imipenem– with newer drugs in clinical trials of cUTI.14,19 cilastatin group. Because the target sample size of the Strengths of our study include its double-blind, aztreonam–nacubactam group was half that of the comparative phase 3 design, which provides a high level cefepime–nacubactam group, the power to detect of evidence; the use of a composite primary outcome of superiority of aztreonam–nacubactam over imipenem– clinical cure and microbiological eradication plus a more cilastatin was insucient, and superiority of stringent definition of microbiologic eradication aztreonam–nacubactam over imipenem–cilastatin was (<10³ CFU/mL on urine culture), which is stricter than not included in the hypotheses to be tested in this study. the primary outcomes used in registrational trials of It was therefore not possible to consider the superiority recently approved treatments for cUTI (eg, cefiderocol,15 of aztreonam–nacubactam. Most patients in this study relebactam,16 and ceftazidime–avibactam17); and the (85% of the microbiological mITT population) were ability of the study to show the superiority of cefepime– located in Eastern Europe. Although it is possible that nacubactam versus imipenem–cilastatin for the regional dierences in susceptibility patterns might treatment of patients hospitalised with cUTI or acute exist, geographical location did not alter either the uncomplicated pyelonephritis. pathophysiological features of cUTI or acute We suggest that treatment dierences observed in the uncomplicated pyelonephritis or the expected response results of the primary composite ecacy endpoint in the to antibacterials, as inclusion in the primary analysis microbiological mITT group are similar to dierences in population required that all study drugs were active ecacy in cases of ESBL-producing bacteria and against the baseline pathogens. Moreover, the secondary bacteraemia. Future studies include ecacy pharmacokinetic profiles are known to be similar analyses in patients with baseline qualifying pathogens between White and Asian (Japanese or Chinese) that were not susceptible to imipenem or meropenem in individuals. Pharmacokinetic data (area under the the present study and the ongoing phase 3 Integral-2 concentration–time curve) for White versus Asian study (NCT05905055), which will assess the ecacy and populations have been described as follows: 1 g safety of cefepime–nacubactam and aztreonam– nacubactam, 118 µg·h/mL22 versus 129 µg·h/mL;23 2 g nacubactam compared with the best available therapy for cefepime, 285 µg·h/mL24 versus 289 µg·h/mL;25 and 2 g adults with infections caused by carbapenem-resistant aztreonam, 294–469 µg·h/mL26 versus 389 µg·h/mL.27 Enterobacterales. Finally, although genomic characterisation of the Regarding safety, the incidences of treatment-emergent resistance mechanisms was performed, the results of adverse events and study drug-related treatment- this analysis are planned to be reported in a future emergent adverse events were lower in the publication. 1938 Articles In conclusion, the composite and microbiological evaluation and for the purpose of achieving the objectives of approved success rate of cefepime–nacubactam at the test of cure proposals. A data use agreement must be concluded. visit showed non-inferiority and superiority versus Acknowledgments imipenem–cilastatin and that of aztreonam–nacubactam The authors thank all investigators and patients involved in this clinical showed non-inferiority versus imipenem–cilastatin. trial programme; Sarah Bubeck, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Meiji Seika Cefepime–nacubactam and aztreonam–nacubactam Pharma, in accordance with Good Publication Practice guidelines were well tolerated and no new safety concerns were (https://www.ismpp.org/gpp-2022); and Marito Araki, of Meiji Seika identified. Thus, cefepime–nacubactam and aztreonam– Pharma, and Hayato Okade, of Meiji Seika Pharma, for providing additional writing support. This research was funded by Meiji Seika nacubactam are potential treatment options for Pharma, and the Japan Agency for Medical Research and Development. patients with cUTI and acute uncomplicated References pyelonephritis caused by Gram-negative bacteria except 1 Zeng Z, Zhan J, Zhang K, Chen H, Cheng S. Global, regional, and Acinetobacter species, including infections caused by national burden of urinary tract infections from 1990 to 2019: antimicrobial-resistant strains. an analysis of the global burden of disease study 2019. World J Urol 2022; 40: 755–63. Contributors 2 Foxman B. Epidemiology of urinary tract infections: incidence, ST, KT, KY, YD, MY, KM, MS, RT, SeK, KK, and HM participated in the morbidity, and economic costs. Dis Mon 2003; 49: 53–70. conception and design of the study and contributed to the writing of the 3 Tamma PD, Heil EL, Justo JA, Mathers AJ, Satlin MJ, Bonomo RA. protocol. KY and HH participated in the study as investigators. ST, MS, Infectious Diseases Society of America 2024 guidance on the RT, KS, SaK, TM, SeK, KK, and HM contributed to study oversight. treatment of antimicrobial-resistant Gram-negative infections. YS performed all statistical elements of the study design and analysis of Clin Infect Dis 2024; published online Aug 7. http://doi.org/10·1093/ the results. SeK and KK were responsible for project administration. cid/ciae403. TN contributed to the funding acquisition. All authors contributed to the 4 Sabih A, Leslie SW. Complicated urinary tract infections. 2024. interpretation of the results. MS led the writing of the initial drafts of the StatPearls Publishing, 2025. manuscript on which all authors commented, and all authors agreed 5 WHO. WHO bacterial priority pathogens list, 2024. 2024. https:// with the decision to submit the final manuscript for publication. iris.who.int/bitstream/handle/10665/376776/9789240093461-eng. ST and KS directly accessed and verified the underlying data, and were pdf?sequence=1 (accessed Sept 29, 2025). responsible for the decision to submit for publication. 6 Yoon YK, Kim JH, Sohn JW, Yang KS, Kim MJ. Role of piperacillin/tazobactam as a carbapenem-sparing antibiotic for Declaration of interests treatment of acute pyelonephritis due to extended-spectrum ST reports grants from Meiji Seika Pharma and Shimadzu; consulting β-lactamase-producing Escherichia coli. Int J Antimicrob Agents fees from Meiji Seika Pharma, Hologic Japan, MSD, Nippon Shinyaku, 2017; 49: 410–15. and Fuji Film Toyama Chemical; honoraria from Meiji Seika Pharma, 7 Wilson APR. Sparing carbapenem usage. J Antimicrob Chemother Shionogi, MSD, Sekisui Medical, Pfizer, Roche Diagnostics, Abbott 2017; 72: 2410–17. Japan, Denka, Sysmex, Asahi Kasei, Fuji Rebio, and Gilead Sciences; 8 Karaiskos I, Giamarellou H. Carbapenem-sparing strategies for payment for expert testimony from GSK; leadership of fiduciary role for ESBL producers: when and how. Antibiotics (Basel) 2020; 9: 61. LSI Medience. KT reports grants, consulting fees, and honoraria from 9 Paul M, Carrara E, Retamar P, et al. European Society of Clinical Meiji Seika Pharma. KY reports grants from Meiji Seika Pharma, Microbiology and Infectious Diseases (ESCMID) guidelines for the consulting fees and honoraria from Meiji Seika Pharma, Shionogi, treatment of infections caused by multidrug-resistant Gram- Daiichi Sankyo Company, Merck Sharp and Dohme, Becton, Dickinson negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect 2022; 28: 521–47. and Company Japan, BioMérieux Japan, Fujifilm Toyama Chemical, GlaxoSmithKline, Kyorin Pharmaceutical, Pfizer, GramEye, 10 Morinaka A, Tsutsumi Y, Yamada M, et al. OP0595, a new diazabicyclooctane: mode of action as a serine β-lactamase inhibitor, Roche Diagnostics, and Eiken Chemical. HH reports grants from Meiji antibiotic and β-lactam ‘enhancer’. J Antimicrob Chemother 2015; Seika. YD reports consulting fees from Meiji Seika Pharma, Shionogi, 70: 2779–86. and GSK; honoraria from Shionogi, Gilead, BD, and Chugai. 11 Miettinen O, Nurminen M. Comparative analysis of two rates. MY reports grants from the Japan Agency for Medical Research and Stat Med 1985; 4: 213–26. Development; Health Labour Sciences Research, and Grant-in-aid for 12 Bonkat G, Bartoletti R, Bruyère F, et al. EAU guidelines on Scientific Research; consulting fees from Meiji Seika Pharma; honoraria urological infections. 2020. https://d56bochluxqnz.cloudfront.net/ from Kyorin Pharmaceutical, Medical & Biological Laboratories, documents/EAU-Guidelines-on-Urological-infections-2020.pdf Shionogi, Kyokuto Pharmaceutical Industrial, Sysmex Corporation, (accessed Sept 29, 2025). Toyobo, and GSK; payment for expert testimony from GSK. 13 Japanese Association for Infectious Disease/Japanese Society of KM reports grants from Meiji Seika Pharma, Sumitomo Pharma, Kyorin Chemotherapy, JAID/JSC Guide/Guidelines to Clinical Pharmaceutical, Earth Corporation, Kenei Pharmaceutical, and Management of Infectious Disease Preparing Committee, Urinary Shionogi; and consulting fees and honoraria from Meiji Seika Pharma. tract infection/male genital infection working group, et al. JAID/ MS, RT, KS, SaK, YS, TM, SeK, KK, and TN report full-time employment JSC guidelines for clinical management of infectious disease and support for attending meetings or travel funded by Meiji Seika 2015—urinary tract infection/male genital infection. Pharma. TN reports board membership at Meiji Seika Pharma. J Infect Chemother 2017; 23: 733–51. HM reports grants from Meiji Seika Pharma, Miyarisan Pharmaceutical, 14 Wagenlehner FM, Gasink LB, McGovern PC, et al; CERTAIN-1 and Kyorin Pharmaceutical; consulting fees from Meiji Seika Pharma; Study Team. Cefepime-taniborbactam in complicated urinary tract and honoraria from Meiji Seika Pharma, Miyarisan Pharmaceutical, infection. N Engl J Med 2024; 390: 611–22. Shionogi, Pfizer Japan, GlaxoSmithKline, Daiichi Sankyo, MSD, Kyorin 15 Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol Pharmaceutical, Gilead Sciences, Sumitomo Pharma, Asahi Kasei versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, Pharma Corporation, Fukoku, Tsumura, Nipro Corporation, and Roche randomised, double-blind, non-inferiority trial. Lancet Infect Dis Diagnostics. 2018; 18: 1319–28. Data sharing 16 Sims M, Mariyanovski V, McLeroth P, et al. 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