Staphylococcus Aureus Bacteremia
Conditions
Keywords
Ceftobiprole, daptomycin, Staphylococcus aureus, Bacteremia, bloodstream infection
Brief summary
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).
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.
Interventions
Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) as a 2 h infusion
DRUGDaptomycin
Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
Sponsors
Department of Health and Human Services
Basilea Pharmaceutica
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With or Without Overall Success at the Post-treatment Evaluation (PTE) Visit | PTE visit on Day 70 (± 5 days) post-randomization | 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): 1. Patient alive at Day 70 (± 5 days) post-randomization. 2. No new metastatic foci or complications of the SAB infection. 3. Resolution or improvement of SAB-related clinical signs and symptoms. 4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Microbiological Eradication at the PTE Visit | At PTE visit on Day 70 (± 5 days) post-randomization | 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. |
| All-cause Mortality at the PTE Visit | At PTE visit on Day 70 (± 5 days) post-randomization | Comparison of all-cause mortality rates in the mITT population |
| Number of Patients With or Without Overall Success at the PTE Visit in the CE Population | At PTE visit on Day 70 (± 5 days) post-randomization | 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): 1. Patient alive at Day 70 (± 5 days) post-randomization. 2. No new metastatic foci or complications of the SAB infection. 3. Resolution or improvement of SAB-related clinical signs and symptoms. 4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus) |
| Time to Staphylococcus Aureus Bloodstream Clearance | Up to 6 weeks post-randomization | 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 |
| Number of Patients With or Without Adverse Events (AEs) | AEs were assessed from the first dose of study drug through the post-treatment evaluation (PTE) visit on Day 70 (± 5 days) | Treatment-emergent adverse events in the safety population |
| Number of Patients With or Without New Metastatic Foci or Other Complications of SAB Developed After Day 7 | Assessment after Day 7 post-randomization through to post-treatment evaluation (PTE) visit on Day 70 (± 5 days) | 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 |
Countries
Argentina, Bulgaria, Colombia, Georgia, Germany, Greece, Israel, Italy, Mexico, Panama, Russia, Serbia, South Africa, Spain, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
Hospitalized male or female patients aged ≥ 18 years who had complicated Staphylococcus aureus bacteremia (SAB). SAB, based on ≥ 1 positive blood culture obtained within 72 h prior to randomization, with signs or symptoms of bloodstream infection
Pre-assignment details
A total of 390 patients were randomized and comprised the Intent-to-Treat (ITT) population (ceftobiprole n = 192; comparator n = 198). Three of these patients were excluded from the modified ITT (mITT) population: one patient in the ceftobiprole group who discontinued prior to receiving study treatment, and two patients in the ceftobiprole group who were determined by central laboratory results not to have a confirmed positive blood culture for Staphylococcus aureus at baseline
Participants by arm
| Arm | Count |
|---|---|
| Ceftobiprole Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril)
Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion | 189 |
| Daptomycin Daptomycin 6 mg/kg, with or without aztreonam
Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam | 198 |
| Total | 387 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative or logistical reason | 1 | 0 |
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 17 | 18 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | The patient was transferred to another hospital | 1 | 0 |
| Overall Study | Withdrawal by Subject | 11 | 6 |
Baseline characteristics
| Characteristic | Ceftobiprole | Daptomycin | Total |
|---|---|---|---|
| Age, Continuous | 55.5 years STANDARD_DEVIATION 15.18 | 56.5 years STANDARD_DEVIATION 15.33 | 56.0 years STANDARD_DEVIATION 15.25 |
| Aztreonam treatment at baseline | 0 Participants | 62 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 15 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 174 Participants | 182 Participants | 356 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Most frequent baseline categories of complicated SAB (Investigator-assessed) Chronic dialysis | 24 Participants | 25 Participants | 49 Participants |
| Most frequent baseline categories of complicated SAB (Investigator-assessed) Definite right-sided endocarditis | 15 Participants | 10 Participants | 25 Participants |
| Most frequent baseline categories of complicated SAB (Investigator-assessed) Intra-abdominal abscess | 26 Participants | 29 Participants | 55 Participants |
| Most frequent baseline categories of complicated SAB (Investigator-assessed) Osteomyelitis | 13 Participants | 17 Participants | 30 Participants |
| Most frequent baseline categories of complicated SAB (Investigator-assessed) Persistent SAB | 16 Participants | 16 Participants | 32 Participants |
| Most frequent baseline categories of complicated SAB (Investigator-assessed) Septic arthritis | 22 Participants | 19 Participants | 41 Participants |
| Most frequent baseline categories of complicated SAB (Investigator-assessed) Skin and skin structure infection | 116 Participants | 121 Participants | 237 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 179 Participants | 192 Participants | 371 Participants |
| Region of Enrollment Central America | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment Europe | 175 Participants | 185 Participants | 360 Participants |
| Region of Enrollment North America | 5 Participants | 5 Participants | 10 Participants |
| Region of Enrollment South Africa | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment South America | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Female | 128 Participants | 140 Participants | 268 Participants |
| Sex: Female, Male Male | 61 Participants | 58 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 17 / 191 | 18 / 198 |
| other Total, other adverse events | 61 / 191 | 45 / 198 |
| serious Total, serious adverse events | 36 / 191 | 45 / 198 |
Outcome results
Primary
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): 1. Patient alive at Day 70 (± 5 days) post-randomization. 2. No new metastatic foci or complications of the SAB infection. 3. Resolution or improvement of SAB-related clinical signs and symptoms. 4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus)
Time frame: PTE visit on Day 70 (± 5 days) post-randomization
Population: The mITT population comprised the subset of patients in the ITT population who received any dose of study medication, and had a blood culture positive for S. aureus at baseline
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ceftobiprole | Number of Patients With or Without Overall Success at the Post-treatment Evaluation (PTE) Visit | Number of responders | 132 Participants |
| Ceftobiprole | Number of Patients With or Without Overall Success at the Post-treatment Evaluation (PTE) Visit | Number of non-responders | 57 Participants |
| Daptomycin | Number of Patients With or Without Overall Success at the Post-treatment Evaluation (PTE) Visit | Number of responders | 136 Participants |
| Daptomycin | Number of Patients With or Without Overall Success at the Post-treatment Evaluation (PTE) Visit | Number of non-responders | 62 Participants |
Comparison: The observed difference in percentage of responders at PTE (ceftobiprole group minus the daptomycin group) were determined and a two-sided 95% confidence interval (CI) for the observed difference was computed, with adjustment for actual stratum (dialysis status and prior antibacterial treatment use). Cochran-Mantel-Haenszel (CMH) weights were used for the stratum weight in the calculation of the CI95% CI: [-7.1, 11.1]
Secondary
All-cause Mortality at the PTE Visit
Comparison of all-cause mortality rates in the mITT population
Time frame: At PTE visit on Day 70 (± 5 days) post-randomization
Population: The mITT population comprised the subset of patients in the ITT population who received any dose of study medication, and had a blood culture positive for S. aureus at baseline
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ceftobiprole | All-cause Mortality at the PTE Visit | Patients died | 17 Participants |
| Ceftobiprole | All-cause Mortality at the PTE Visit | Patients alive | 172 Participants |
| Daptomycin | All-cause Mortality at the PTE Visit | Patients died | 18 Participants |
| Daptomycin | All-cause Mortality at the PTE Visit | Patients alive | 180 Participants |
95% CI: [-6.2, 5.2]
Secondary
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.
Time frame: At PTE visit on Day 70 (± 5 days) post-randomization
Population: The mITT population comprised the subset of patients in the ITT population who received any dose of study medication, and had a blood culture positive for S. aureus at baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ceftobiprole | Number of Patients With Microbiological Eradication at the PTE Visit | 155 Participants |
| Daptomycin | Number of Patients With Microbiological Eradication at the PTE Visit | 153 Participants |
95% CI: [-2.9, 13]
Secondary
Number of Patients With or Without Adverse Events (AEs)
Treatment-emergent adverse events in the safety population
Time frame: AEs were assessed from the first dose of study drug through the post-treatment evaluation (PTE) visit on Day 70 (± 5 days)
Population: The Safety population comprised all randomized patients who received any dose of study drug. Patients in the Safety population were analyzed according to the first study drug received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Any drug-related AE | 25 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Any AE leading to treatment discontinuation | 18 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Any study drug-related severe AEs | 1 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Study drug-related AEs leading to treatment discontinuation | 9 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Any adverse events (AEs) | 121 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Any AE leading to death | 17 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Any serious adverse events (SAE) | 36 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Study drug-related AEs leading to death | 0 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Any severe AEs | 29 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Any AE of special interest (AESI) | 9 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Any drug-related SAEs | 2 Participants |
| Ceftobiprole | Number of Patients With or Without Adverse Events (AEs) | Any drug-related AESI | 5 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Any drug-related SAEs | 4 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Any severe AEs | 38 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Any adverse events (AEs) | 117 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Any drug-related AE | 11 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Any study drug-related severe AEs | 2 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Any serious adverse events (SAE) | 45 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Any drug-related AESI | 4 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Any AE leading to treatment discontinuation | 18 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Study drug-related AEs leading to treatment discontinuation | 3 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Any AE leading to death | 18 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Study drug-related AEs leading to death | 0 Participants |
| Daptomycin | Number of Patients With or Without Adverse Events (AEs) | Any AE of special interest (AESI) | 7 Participants |
Secondary
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
Time frame: Assessment after Day 7 post-randomization through to post-treatment evaluation (PTE) visit on Day 70 (± 5 days)
Population: The mITT population comprised the subset of patients in the ITT population who received any dose of study medication, and had a blood culture positive for S. aureus at baseline
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ceftobiprole | Number of Patients With or Without New Metastatic Foci or Other Complications of SAB Developed After Day 7 | Patients with development of new metastatic foci or other complications of SAB after Day 7 | 11 Participants |
| Ceftobiprole | Number of Patients With or Without New Metastatic Foci or Other Complications of SAB Developed After Day 7 | Patients without development of new metastatic foci or other complications of SAB after Day 7 | 178 Participants |
| Daptomycin | Number of Patients With or Without New Metastatic Foci or Other Complications of SAB Developed After Day 7 | Patients with development of new metastatic foci or other complications of SAB after Day 7 | 11 Participants |
| Daptomycin | Number of Patients With or Without New Metastatic Foci or Other Complications of SAB Developed After Day 7 | Patients without development of new metastatic foci or other complications of SAB after Day 7 | 187 Participants |
95% CI: [-4.6, 4.8]
Secondary
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): 1. Patient alive at Day 70 (± 5 days) post-randomization. 2. No new metastatic foci or complications of the SAB infection. 3. Resolution or improvement of SAB-related clinical signs and symptoms. 4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus)
Time frame: At PTE visit on Day 70 (± 5 days) post-randomization
Population: The CE population comprised the subset of patients in the mITT population who complied with important pre-specified aspects of the study
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ceftobiprole | Number of Patients With or Without Overall Success at the PTE Visit in the CE Population | Number of responders | 127 Participants |
| Ceftobiprole | Number of Patients With or Without Overall Success at the PTE Visit in the CE Population | Number of non-responders | 36 Participants |
| Daptomycin | Number of Patients With or Without Overall Success at the PTE Visit in the CE Population | Number of responders | 130 Participants |
| Daptomycin | Number of Patients With or Without Overall Success at the PTE Visit in the CE Population | Number of non-responders | 37 Participants |
95% CI: [-8.3, 9.5]
Secondary
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
Time frame: Up to 6 weeks post-randomization
Population: The mITT population comprised the subset of patients in the ITT population who received any dose of study medication, and had a blood culture positive for S. aureus at baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ceftobiprole | Time to Staphylococcus Aureus Bloodstream Clearance | 4 Days |
| Daptomycin | Time to Staphylococcus Aureus Bloodstream Clearance | 4 Days |