Ceftobiprole in the Treatment of Patients With Staphylococcus Aureus Bacteremia

A Randomized, Double-blind, Multi-center Study to Establish the Efficacy and Safety of Ceftobiprole Medocaril Compared to Daptomycin in the Treatment of Staphylococcus Aureus Bacteremia, Including Infective Endocarditis

The purpose of this study was to compare the efficacy and safety of ceftobiprole medocaril versus a comparator in the treatment of patients with complicated Staphylococcus aureus bacteremia (SAB).

Study Overview

• Status: Completed
• Conditions: Staphylococcus Aureus Bacteremia
• Intervention / Treatment: Drug: Ceftobiprole medocaril; Drug: Daptomycin

Detailed Description

Patients were randomized 1:1 to ceftobiprole or the comparator regimen. Randomization was stratified by study site, dialysis status, and prior antibacterial treatment use within 7 days before randomization.

The three phases of the study were:

1. Screening assessments of up to 72 hours prior to randomization
2. Randomization and subsequent active treatment with intravenous (i.v.) study drug (ceftobiprole or daptomycin ± aztreonam).
3. Post-treatment, comprising an end of trial (EOT) visit (within 72 hours of last study-drug administration), Day 35 (± 3 days), Day 42 (± 3 days), and a post-treatment evaluation (PTE) visit on Day 70 (± 5 days) post-randomization.

• Study Type: Interventional
• Enrollment (Actual): 390
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 81641
    • Central Hospital de San Isidro Melchor Posse
  • La Plata, Argentina, B1900AVG
    • Medical Institute Platense SA
  • Rosario, Argentina, S2000CVB
    • British Sanatorium SA
• Bulgaria
  • Plovdiv, Bulgaria, 4004
    • University Multiprofile Hospital for Active Treatment "Eurohospital Plovdiv", Plovdiv, Intensive Care Clinic
  • Ruse, Bulgaria, 7002
    • University Multiprofile Hospital for Active Treatment 'Kanev', Ruse, Department of General, Purulent-Septic, Pediatric and One Day Surgery
  • Sliven, Bulgaria, 8800
    • Multiprofile Hospital for Active Treatment "Dr. Ivan Seliminski", Sliven, Anesthesiology and Intensive Care Department
  • Sofia, Bulgaria, 1606
    • University Multiprofile Hospital for Active Treatment and Emergency Medicine "N.I. Pirogov", Sofia, Clinic of Purulent-Septic Surgery
• Colombia
  • Barranquilla, Colombia, 080020
    • De La Costa Clinic Ltd.
• Georgia
  • Rustavi, Georgia, 3700
    • JSC Rustavi Central Hospital
  • Tbilisi, Georgia, 0159
    • LTD Institute of Clinical Cardiology
  • Tbilisi, Georgia, 0160
    • LTD Central University Clinic After Academic N. Kipshidze
  • Tbilisi, Georgia, 0144
    • LTD High Technology Medical Center University Clinic
  • Tbilisi, Georgia, 0159
    • LTD Academician G. Chapidze Emergency Cardiology Center
  • Tbilisi, Georgia, 0160
    • LTD Academician Vakhtang Bochorishvili Clinic
  • Tbilisi, Georgia, 0191
    • LTD N 5 Clinikal Hospital
• Germany
  • Regensburg, Germany, 93053
    • University Hospital Regensburg, Department of Infectious Diseases
• Greece
  • Athens, Greece, 11527
    • "LAIKO" General Hospital, 1st Department of Internal Medicine
• Israel
  • Haifa, Israel, 31048
    • Bnai Zion Medical Center
  • Poriyya 'Illit, Israel, 1520800
    • The Baruch Padeh Medical Center
  • Ramat Gan, Israel, 5262000
    • Chaim Sheba Medical Center
  • Safed, Israel, 1311001
    • Sieff Medical Center
  • Tel Aviv, Israel, 64239
    • Sourasky Medical Center
• Italy
  • Genoa, Italy, 16132
    • IRCCS-University Hospital San Martino-IST, Infectious Diseases Division
  • Monza, Italy, 20900
    • University of Milan-Bicocca- S.Gerardo Hospital
  • Trieste, Italy, 34125
    • Giuliano Isontina University Health Authority
  • Udine, Italy, 33100
    • Central Friuli University Healthcare Company
• Mexico
  • Guadalajara, Mexico, 44280
    • Fray Antonio Alcalde Guadalajara Civil Hospital
  • Monterrey, Mexico, 64460
    • Dr. Jose Eleuterio Gonzalez Monterrey University Hospital
• Panama
  • Panamá, Panama, 32401
    • INDICASAT SMO / Santo Tomas Hospital, Investigation Department
• Russian Federation
  • Belgorod, Russian Federation, 308007
    • St. Joseph Belgorod Regional Clinical Hospital
  • Moscow, Russian Federation, 117292
    • Vinogradov Moscow Municipal Hospital, Department of Surgery #14
  • Moscow, Russian Federation, 119049
    • N.I. Pirogov City Clinical Hospital #1
  • Moscow, Russian Federation, 121359
    • Federal State Budget Institution "Central Clinical Hospital with Polyclinic" under the Presidential Executive Office of Russian Federation
  • Moscow, Russian Federation, 123423
    • L.A. Vorokhobov City Clinical Hospital #67
  • Nizhny Novgorod, Russian Federation, 603076
    • City Hospital #33
  • Pyatigorsk, Russian Federation, 357500
    • Pyatigorsk City Clinical Hospital
  • Yaroslavl, Russian Federation, 150062
    • Regional Clinical Hospital
• Serbia
  • Belgrade, Serbia, 11000
    • Zvezdara University Medical Center, Clinic of Internal Diseases, Clinical Department of Nephrology and Metabolic Disorders with Dialysis "Prof. dr Vasilije Jovanovic"
  • Kragujevac, Serbia, 34000
    • Clinical Center Kragujevac, Center for Anesthesia and Reanimation
• South Africa
  • Benoni, South Africa, 1501
    • Worthwhile Clinical Trials, Lakeview Hospital
  • Tongaat, South Africa, 4400
    • Mediclinic Victoria - Practice of R Moodley and MI Sarwan
• Spain
  • Barcelona, Spain, 080003
    • Hospital del Mar, Department of Intensive Care
  • Elche, Spain, 03203
    • University Hospital de Elche, Infectious Diseases Unit
  • Madrid, Spain, 28007
    • General University Hospital Gregorio Maranon, Infectious Diseases / Internal Medicine
  • Madrid, Spain, 28034
    • University Hospital Ramon y Cajal, Department of Infectious Diseases
  • Terrassa, Spain, 08221
    • University Hospital Mutua de Terrassa, Unit of Infectious Diseases
• Turkey
  • Istanbul, Turkey, 34846
    • Istanbul Kartal Kosuyolu Yuksek Ihtisas Training and Research Hospital
  • Samsun, Turkey, 55139
    • Ondokuz Mayis University School of Medicine, Department of Infectious Diseases
• Ukraine
  • Dnipro, Ukraine, 49102
    • Dnipropetrovsk City Multispecialty Clinical Hospital #4
  • Dnipro, Ukraine, 49027
    • Dnipropetrovsk I.I. Mechnykov Regional Clinical Hospital
  • Ivano-Frankivs'k, Ukraine, 76008
    • Ivano-Frankivsk Regional Clinical Hospital
  • Kharkiv, Ukraine, 61018
    • V.T. Zaitsev Institute of General and Emergency Surgery
  • Kharkiv, Ukraine, 61037
    • Public Non-Profit Enterprise: O.O. Shalimov City Clinical Hospital #2 under Kharkiv City Council
  • Vinnytsia, Ukraine, 21018
    • Communal Nonprofit Enterprise "Vinnytsia Regional Clinical Hospital named after N.I. Pirogov Vinnytsia Regional Council"
  • Zaporizhzhya, Ukraine, 69032
    • City Clinical Hospital #3
• United States
  • California
    • Chula Vista, California, United States, 91911
      • eStudy Site - Chula Vista - PPDS
  • Florida
    • West Palm Beach, Florida, United States, 33407
      • Triple O Medical Services Inc
  • Montana
    • Butte, Montana, United States, 59701
      • Mercury Street Medical Group
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • eStudy Site - Las Vegas - PPDS
  • Ohio
    • Columbus, Ohio, United States, 43214
      • Remington Davis Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female ≥ 18 years of age
• Staphylococcus aureus bacteremia (SAB), based on at least one positive blood culture obtained within the 72 h prior to randomization

• At least one of the following signs or symptoms of bacteremia:

  1. fever (e.g.≥ 38 °C/100.4 °F measured orally)
  2. white blood cell count > 10,000 or < 4,000 cells/µL, or > 10% immature neutrophils (bands)
  3. tachycardia (heart rate > 90 bpm)
  4. hypotension (systolic blood pressure < 90 mmHg)

• At least one of the following:

  1. SAB in patients undergoing chronic intermittent hemodialysis or peritoneal dialysis
  2. Persistent SAB
  3. Definite native-valve right-sided infective endocarditis by Modified Duke's Criteria
  4. Other forms of complicated SAB
  5. Osteomyelitis (including vertebral, sternal, or long-bone osteomyelitis)
  6. Epidural or cerebral abscess
• Other inclusion criteria have been applied

Exclusion Criteria:

• Treatment with potentially effective (anti-staphylococcal) systemic antibacterial treatment for more than 48 h within the 7 days prior to randomization; Exception: Documented failure of bloodstream clearance
• Bloodstream or non-bloodstream concomitant infections with Gram-negative bacteria that are known to be non-susceptible to either ceftobiprole or aztreonam
• Left-sided infective endocarditis
• Prosthetic cardiac valves or valve support rings, cardiac pacemakers, automatic implantable cardioverter-defibrillator, or left-ventricular assist devices
• Community- or hospital-acquired pneumonia
• Opportunistic infections within 30 days prior to randomization, where the underlying cause of these infections is still active
• Requirement for continuous renal-replacement therapy
• Women who are pregnant or nursing
• Other exclusion criteria have been applied

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ceftobiprole medocaril; Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril)	Drug: Ceftobiprole medocaril; Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) as a 2 h infusion
Active Comparator: Daptomycin; Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards), with or without aztreonam	Drug: Daptomycin; Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With or Without Overall Success at the Post-treatment Evaluation (PTE) Visit	Comparison of overall success rates in the mITT population Overall success at PTE for the mITT population was defined as all of the following criteria being met (Responder): Patient alive at Day 70 (± 5 days) post-randomization.; No new metastatic foci or complications of the SAB infection.; Resolution or improvement of SAB-related clinical signs and symptoms.; Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus)	PTE visit on Day 70 (± 5 days) post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With or Without Overall Success at the PTE Visit in the CE Population	Comparison of overall success rates in the Clinical Evaluable (CE) population Overall success at PTE for the CE population was defined as all of the following criteria being met (Responder): Patient alive at Day 70 (± 5 days) post-randomization.; No new metastatic foci or complications of the SAB infection.; Resolution or improvement of SAB-related clinical signs and symptoms.; Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus)	At PTE visit on Day 70 (± 5 days) post-randomization
Number of Patients With Microbiological Eradication at the PTE Visit	Comparison of microbiological eradication rates in the mITT population. Microbiological eradication rate was defined as a negative blood culture for S. aureus during study treatment and another negative blood culture during the follow up period up to PTE.	At PTE visit on Day 70 (± 5 days) post-randomization
All-cause Mortality at the PTE Visit	Comparison of all-cause mortality rates in the mITT population	At PTE visit on Day 70 (± 5 days) post-randomization
Number of Patients With or Without New Metastatic Foci or Other Complications of SAB Developed After Day 7	Comparison of complication rates in the mITT population defined by number of patients with development of new metastatic foci or other complications of SAB after Day 7	Assessment after Day 7 post-randomization through to post-treatment evaluation (PTE) visit on Day 70 (± 5 days)
Time to Staphylococcus Aureus Bloodstream Clearance	Time-to-event in the mITT Bloodstream clearance was defined as two consecutive study days with blood-culture-negative assessments for S. aureus, without any subsequent S. aureus relapse or reinfection	Up to 6 weeks post-randomization
Number of Patients With or Without Adverse Events (AEs)	Treatment-emergent adverse events in the safety population	AEs were assessed from the first dose of study drug through the post-treatment evaluation (PTE) visit on Day 70 (± 5 days)

Collaborators and Investigators

• Sponsor: Basilea Pharmaceutica
• Collaborators: Department of Health and Human Services
• Investigators: Study Director: Marc Engelhardt, MD, Basilea Pharmaceutica

Publications and helpful links

General Publications

• Hamed K, Engelhardt M, Jones ME, Saulay M, Holland TL, Seifert H, Fowler VG Jr. Ceftobiprole versus daptomycin in Staphylococcus aureus bacteremia: a novel protocol for a double-blind, Phase III trial. Future Microbiol. 2020 Jan;15(1):35-48. doi: 10.2217/fmb-2019-0332. Epub 2020 Jan 10.
• Holland TL, Cosgrove SE, Doernberg SB, Jenkins TC, Turner NA, Boucher HW, Pavlov O, Titov I, Kosulnykov S, Atanasov B, Poromanski I, Makhviladze M, Anderzhanova A, Stryjewski ME, Assadi Gehr M, Engelhardt M, Hamed K, Ionescu D, Jones M, Saulay M, Smart J, Seifert H, Fowler VG Jr; ERADICATE Study Group. Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia. N Engl J Med. 2023 Oct 12;389(15):1390-1401. doi: 10.1056/NEJMoa2300220. Epub 2023 Sep 27.

Helpful Links

• Ceftobiprole versus daptomycin in Staphylococcus aureus bacteremia: a novel protocol for a double-blind, Phase III trial
• Abstract; LB2302. Ceftobiprole Compared to Daptomycin With or Without Optional Aztreonam for the Treatment of Complicated Staphylococcus aureus (SAB): Results of a Phase 3, Randomized, Double-Blind Trial (ERADICATE)

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2018
• Primary Completion (Actual): March 11, 2022
• Study Completion (Actual): March 11, 2022

Study Registration Dates

• First Submitted: April 27, 2017
• First Submitted That Met QC Criteria: April 29, 2017
• First Posted (Actual): May 3, 2017

Study Record Updates

• Last Update Posted (Actual): November 8, 2023
• Last Update Submitted That Met QC Criteria: October 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Ceftobiprole, daptomycin, Staphylococcus aureus; Bacteremia, bloodstream infection
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Sepsis; Bacteremia; Staphylococcal Infections; Anti-Infective Agents; Anti-Bacterial Agents; Daptomycin; Ceftobiprole; Ceftobiprole medocaril
• Other Study ID Numbers: BPR-CS-009

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No