Infections Caused by Carbapenem-resistant Gram-negative Pathogens
Conditions
Interventions
Cefiderocol Group:Cefiderocol 2.0g, Q8h , iv gtt, 7-14 Days
Plus:
Meropenem 1.0g (For the treatment of HAP/VAP/HCAP, neutropenia-combined infection, cIAI, and BSI) or 0.5g (For the treatment of cUTI), Q8h, iv gtt, 7~14 days.
Colistin Group:Colistimethate sodium(CMS) 9 million IU/day, iv gtt, in 2-3 divided doses (In patients who are critically ill, a loading dose of 9 million IU should be administered), 7-14 Days.
Plus:
Sponsors
Huashan Hospital, Fudan University
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: General Inclusion Criteria: Patients who meet the following criteria at screening are eligible for enrollment in this study: 1. Hospitalized male and female patients, >=18 years at the time of signing the informed consent. 2. Patients who have provided written informed consent, or whose legal guardian has provided informed consent (if the patient has no capacity for civil conduct, the written informed consent of his guardian shall be obtained; If the patient has limited capacity for civil conduct, the written informed consent of the patient and his/her guardian shall be obtained with the consent of his/her guardian on behalf of the patient. If the patient is unable to read or their guardian is unable to read, an impartial witness should be present at all times throughout the informed consent discussion). 3. Patients must have a confirmed diagnosis of infection (HAP/VAP/HCAP, cIAI, cUTI, or BSI) caused by a carbapenem-resistant gram-negative pathogen prior to randomization. Note: In this study, resistance is defined as "insensitive", i.e., resistance includes intermediate breakpoints (intermediaries) to carbapenem antibiotics. Strains judged to be intermediary but not completely susceptible will be considered carbapenem resistant. Rapid diagnostic tests (e.g., Xpert® Carba-R Assay, CHROMagar mSuperCARBA, RAPIDEC® CARBA NP, NG-Test® CARBA 5) carbapenemase can be used to identify carbapenem-resistant gram-negative infections until a minimum inhibitory concentration (MIC) result for specific infection is available. Based on the breakpoint of carbapenems (e.g., meropenem, imipenem), target pathogens have been identified as carbapenem-resistant gram-negative pathogens. Patients who have received empiric therapy are also eligible for enrollment if they have failed empiric therapy (definition: duration of treatment within 72 hours prior to randomization >48 hours with worsening symptoms and/or signs or no apparent response), or duration of treatment within 72 hours prior to randomization 48 hours and worsening of baseline symptoms and/or signs or no significant response, these patients are eligible for this study. For patients with empiric treatment failure, appropriate microbiology samples obtained within 5 days prior to randomization in this study may be used as screening/baseline samples. Samples should be taken again after randomization (before the first dose of study drug is given). For patients who have received a potentially effective antibiotic regimen for carbapenem-resistant gram-negative bacterial infection, appropriate microbiological samples obtained within 5 days prior to randomization in this study may be used as screening/baseline samples. Samples should be taken again after randomization (before the first dose of study drug is given). 6. Females of childbearing potential must agree to use a medically acceptable contraceptive regimen from the start of study treatment (at least from the first day of the last normal menstru
Exclusion criteria
Exclusion criteria: General Exclusion Criteria: Patients who meet any of the following criteria at screening are not allowed to be enrolled in this study: 1. Patient has a history of allergy to cephalosporins (regardless of the severity of the allergic reaction); or the patient has a history of severe hypersensitivity to any other ß-lactam (e.g., penicillin, monocyclic ß-lactam, or carbapenem). 2. Patients who require > 2 systemic antibiotics to treat gram-negative bacterial infections. Note: Patients with anaerobic and/or gram-positive infections may require concomitant use of appropriate narrow-spectrum antibiotics (e.g., vancomycin, linezolid, metronidazole, clindamycin) and are also eligible for enrollment if these patients require 3 weeks of antibiotic treatment (e.g., bone and joint infections, endocarditis). 7. Patients with cystic fibrosis or moderate to severe bronchiectasis. Note: Patients with severe COPD should also be excluded. 8. Patients in shock at screening. 9. Abnormalities in one or more of the following laboratory tests at baseline: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) >3× upper limit of normal (ULN); Total bilirubin level >2×ULN; Creatinine clearance (CrCL) 30 points. 12. Patients who, in the opinion of the investigator, cannot survive for > 28 days. 13. Patients with carbapenem-resistant gram-negative bacterial infection with potentially effective antibiotics within 72 hours prior to randomization with a treatment duration of 24~48 hours, or with potentially effective antibiotics for carbapenem-resistant gram-negative bacterial infections with a treatment duration of > within 72 hours prior to randomization= Patients who have responded significantly for 48 hours. 14. Patient has, in the opinion of the investigator, any condition or circumstance capable of affecting patient safety or the quality of study data. 15. Patients who have been treated with other investigational drugs or devices within 30 days prior to enrollment in the study. 16. Patients who have previously been randomized or treated with cefdil in this study. 17. Patients who are undergoing peritoneal dialysis, hemodialysis, or hemofiltration. 18. Patients who meet the special exclusion criteria for each site of infection (see Special Exclusion Criteria for Sites of Infection). Site-specific inclusion and exclusion criteria: HAP/VPA/HCP Special Exclusion Criteria: Patients who meet any of the following criteria at screen
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To assess, at Test of Cure (TOC), the clinical outcome of treatment with cefiderocol or colistin with hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP)/healthcare-associated pneumonia (HCAP), complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or bloodstream infections (BSI) caused by carbapenem-resistant Gram-negative pathogens;To assess, at TOC, the microbiological eradication of treatment with cefiderocol or colistin with HAP/VAP/HCAP, cIAI, cUTI, or BSI caused by carbapenem-resistant Gram-negative pathogens;To assess the composite response of clinical response and microbiological eradication of treatment with cefiderocol or colistin in subjects with cUTI at TOC;To assess the all-cause mortality at Day 14 and Day 28; | — |
Secondary
| Measure | Time frame |
|---|---|
| To assess the safety of cefiderocol;To assess the change or stop of antibiotic treatment due to drug-related renal toxicity;To assess the clinical outcome of treatment with cefiderocol or colistin at End of Treatment (EOT) and Follow-up (FUP);To assess the clinical outcome per pathogen of treatment with cefiderocol or colistin at EOT, TOC, and FUP;To assess the microbiologic outcome of treatment with cefiderocol or colistin at EOT and FUP;To assess the clinical outcome of treatment with cefiderocol or colistin in subjects with cIAI at Day 14 and Day 28;To assess the composite response of clinical response and microbiological eradication of treatment with cefiderocol or colistin in subjects with cUTI at EOT, and FUP;To assess the microbiologic outcome of treatment with cefiderocol or colistin in subjects with BSI (regardless of the primary infection diagnosis) at Early Assessment (EA), EOT, TOC, and FUP;To assess the composite response of clinical response and microbiological eradication of treatment in subjects with HAP/VAP/HCAP, cIAI, and BSI, respectively, at TOC;To assess the relationship between the pharmacodynamic (PD) parameter %fT>MIC (percentage of the dosing interval for which the free-drug concentration in plasma exceeds the minimum inhibitory concentration) of cefiderocol based on plasma drug concentrations at steady state and the clinical and microbiologic outcomes of treatment with cefiderocol;To assess cefiderocol and colistin based on the composite endpoint of survival and no change in antibiotic treatment (e.g., daily dosage, dosing frequency, treatment drug/therapy) due to either lack of therapeutic benefit or drug-related toxicity at EOT and TOC;To assess the changes from baseline of Clinical Pulmonary Infection Score (CPIS) parameters at EOT and TOC (HAP/VAP/HCAP only);To assess the changes from baseline of Sequential Organ Failure Assessment (SOFA) score at EOT and TOC;To assess the resource utilization required for the treatment of the study-qua | — |
Countries
China
Contacts
Public ContactZhang Yingyuan / Huang Haihui
Huashan Hospital, Fudan University
Outcome results
None listed