Ceftobiprole in the Treatment of Patients With Acute Bacterial Skin and Skin Structure Infections
Condition: Acute Bacterial Skin and Skin Structure Infections
MeSH terms: Infections; Communicable Diseases; Skin Diseases, Bacterial
Intervention: ceftobiprole medocaril; vancomycin+aztreonam
Intervention description: ceftobiprole 500 mg was to be administered every 8 hours as a 2-hour IV infusion (with dose adjustment for renal impairment). The treatment duration was for a minimum of 5 days and a maximum of 10 days. Treatment could be extended up to 14 days if in the investigator's opinion this was required, and the extension was approved by the sponsor's medical monitor.; Vancomycin 1000 mg (or 15 mg/kg) was to be administered every 12 hours (with dose adjustment for renal impairment) as 2-hour IV infusion. Vancomycin dose adjustment for morbidly obese and hypermetabolic patients was to be done according to local standard of care. When locally available, vancomycin trough testing (VTT) might have been used by the unblinded pharmacist or delegate to adjust the vancomycin dose. The treatment duration was for a minimum of 5 days and a maximum of 10 days. Treatment could be extended up to 14 days if in the investigator's opinion this was required, and the extension was approved by the sponsor's medical monitor.
Aztreonam 1000 mg was to be administered as a 0.5-hour IV infusion every 12 hours. If CLCR was < 30 mL/min (i.e., severe renal impairment), the aztreonam dosage regimen was to be adjusted. The requirement to continue aztreonam therapy beyond Day 3 was to be reassessed at the 72-hour study visit.
Intervention MeSH terms: Vancomycin; Aztreonam; Ceftobiprole; Ceftobiprole medocaril; Cephalosporins
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 679.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This was a randomized, double-blind, active-controlled, parallel-group, multicenter study in
      adult hospitalized patients to establish the safety and efficacy of ceftobiprole medocaril
      compared with vancomycin plus aztreonam in the treatment of acute bacterial skin and skin
      structure infections (ABSSSIs).
    

Eligibility criteria:

        INCLUSION CRITERIA

          1. Male or female, aged ≥18 years.

          2. Diagnosis of ABSSSI, meeting at least one of the definitions in (a) to (c) below.
             Local symptoms must have started within the 7 days prior to the Screening visit:

               1. Cellulitis/erysipelas, defined as a diffuse skin infection characterized by all
                  of the following within 24 hours:

                    -  i. Rapidly spreading areas of erythema, edema, and/or induration with a
                       minimum total lesion surface area of 75cm^2

                    -  ii. No collection of pus apparent upon visual examination

                    -  iii. At least two of the following local signs of infection:

                         -  erythema

                         -  induration

                         -  localized warmth

                         -  pain or tenderness on palpation

                         -  swelling/edema

               2. Major cutaneous abscess, defined as infection characterized by a collection of
                  pus within the dermis or deeper that is apparent upon visual examination before
                  or after therapeutic intervention and is accompanied by all of the following
                  within 24 hours:

                    -  i. Erythema, edema and/or induration with a minimum total lesion surface
                       area of 75 cm^2.

                    -  ii. At least two of the following local signs of infection:

                         -  fluctuance

                         -  incision and drainage required

                         -  purulent or seropurulent drainage

                         -  localized warmth

                         -  pain or tenderness on palpation

               3. Wound infection, defined as infection of any apparent break in the skin
                  characterized by at least one of the following:

                    -  i. Superficial incision/surgical site infection meeting all of the following
                       criteria:

                         -  involves only the skin or subcutaneous tissue around the incision (does
                            not involve fascia).

                         -  occurs within 30 days of procedure.

                         -  purulent drainage (spontaneous or therapeutic) with surrounding
                            erythema, edema and/ or induration with a minimum total lesion surface
                            area of 75cm^2.

                    -  ii. Post-traumatic wound (including penetrating trauma, e.g., needle, nail,
                       knife, insect and spider bites) meeting the following criterion within 24
                       hours:

                         -  Purulent drainage (spontaneous or therapeutic) with surrounding
                            erythema, edema and/or induration with a minimum total lesion surface
                            area of 75cm^2.

          3. At least one of the following regional or systemic signs of infection at the Screening
             visit:

               1. Lymph node tenderness and volume increase, or palpable lymph node proximal to the
                  primary ABSSSI.

               2. Fever > 38 °C/100.4 °F measured orally, > 38.5 °C / 101.3 °F measured
                  tympanically, > 37.5 °C / 99.5 °F measured by the axillary method, or > 39 °C /
                  102.2 °F measured rectally.

               3. White blood cell (WBC) count > 10.0 × 10^9/L or < 4.0 × 10^9/L.

               4. > 10% immature neutrophils (band forms).

          4. Requirement for IV antibacterial treatment.

          5. Willing and able to adhere to study procedures (including prohibitions and
             restrictions) as specified in this protocol.

          6. Willing and able to remain hospitalized (in a hospital or equivalent medical
             confinement or clinical research unit) until completion of the early-clinical-response
             assessment for the primary endpoint.

          7. Informed consent signed by the patient, or their legally acceptable representative if
             appropriate, indicating that they understand the purpose of, and procedures required
             for, the study, and are willing to participate.

        EXCLUSION CRITERIA

        Patients meeting any one of the following:

          1. Use of any systemic antibacterial treatment within 14 days, or topical antibacterial
             administration on the primary lesion within 96 hours, before first infusion of study
             drug.

             Exception: Receipt of a single dose of a short acting (half-life ≤ 12 hours)
             antibacterial therapy (e.g., for surgical prophylaxis) within > 3 days before
             randomization (i.e., patients cannot have received any antibacterial treatment within
             72 hours of randomization).

          2. Contraindication to the administration of either of the study treatments, including
             known clinically-relevant hypersensitivity to related antibacterial treatments (e.g.,
             beta-lactam and glycopeptide antibiotics), or to metronidazole if required as
             adjunctive therapy.

          3. Participation in any other clinical study within the 30 days prior to randomization,
             or any prior participation in this study.

          4. The primary ABSSSI is an uncomplicated skin and skin structure infection, such as
             furuncles, minor abscesses (area of suppuration not surrounded by
             cellulitis/erysipelas), impetiginous lesions, superficial or limited
             cellulitis/erysipelas, or minor wound infections (e.g., stitch abscesses).

          5. The primary ABSSSI is due to, or associated with, any of the following:

               1. Diabetic foot infection, gangrene, or perianal abscess.

               2. Concomitant infection at another site (e.g., septic arthritis, endocarditis,
                  osteomyelitis), not including a secondary ABSSSI lesion.

               3. Infected burns.

               4. Decubitus or chronic skin ulcer, or ischemic ulcer due to peripheral vascular
                  disease (arterial or venous).

               5. Any evolving necrotizing process (e.g., necrotizing fasciitis).

               6. Infections at vascular catheter sites, or involving thrombophlebitis.

          6. The primary ABSSSI is associated with, or in close proximity to, a prosthetic device.

          7. Patients who are placed in a hyperbaric chamber as adjunctive therapy for the ABSSSI.

          8. Patients expected to require more than two surgical interventions in the operating
             room for the ABSSSI.

          9. Severe sepsis or septic shock.

         10. Significant or life-threatening condition (e.g., endocarditis, meningitis) that would
             confound, or interfere with, the assessment of the ABSSSI.

         11. Another severe, acute or chronic medical condition, psychiatric condition, or
             laboratory abnormality that may increase the risks associated with study participation
             or administration of the investigational product, or may interfere with the
             interpretation of study results, and which, in the judgment of the investigator, would
             make the patient inappropriate for entry into this study.

         12. Receiving treatment for active tuberculosis.

         13. Absolute neutrophil count < 0.5 × 10^9/L.

         14. Recent history of opportunistic infections (i.e., within 30 days) if the underlying
             cause of these infections is still active (e.g., leukemia, transplant, acquired
             immunodeficiency syndrome [AIDS]).

         15. Patients receiving systemic steroids (> 40 mg per day prednisolone, or equivalent), or
             receiving immunosuppressant drugs.

         16. Requirement for peritoneal dialysis, plasmapheresis, hemodialysis, venovenous
             dialysis, or other forms of renal filtration, or expected to require such treatment
             before the TOC visit.

         17. Alanine transaminase (ALT) or aspartate transaminase (AST) levels ≥ 8× the upper limit
             of normal, OR severe hepatic disease with Child-Pugh class C.

         18. Women who are pregnant or nursing.

         19. Women who are of childbearing potential and unwilling to use an acceptable method of
             birth control during the study: female sterilization (bilateral tubal occlusion or
             oophorectomy, or hysterectomy) or male partner vasectomy; intrauterine device (IUD);
             combined (estrogen and progesterone containing) hormonal contraception (oral, vaginal
             ring, or transdermal patch) with an ethinylestradiol dose of at least 30 µg, plus use
             of male condoms (preferably with spermicides), female condoms, a female diaphragm or a
             cervical cap; or total sexual abstinence.

             Women are not considered to be of childbearing potential if they are either ≥ 1 year
             post-menopausal (where menopause is defined as at least 12 months of amenorrhea), or
             have a serum follicle stimulating hormone (FSH) measurement consistent with
             post-menopausal status according to local laboratory thresholds. An FSH measurement at
             Screening is to be obtained for post-menopausal females aged < 50 years, or for those
             aged ≥ 50 years who have been post-menopausal for < 2 years.

         20. Inability to start study-drug therapy within 24 hours of Screening.

         21. Patients with illicit drug use within 12 months of screening, including heroin, other
             opioids (unless prescribed for medical reasons unrelated to heroin substitution),
             cocaine / crack cocaine, and amphetamine or methamphetamine. Exception: Cannabis use.