Ceftolozane/Tazobactam (MK-7625A) Plus Metronidazole Versus Meropenem for Participants With Complicated Intra-abdominal Infection (MK-7625A-015)
Condition: Complicated Intra-abdominal Infections
MeSH terms: Infections; Communicable Diseases; Intraabdominal Infections
Intervention: Ceftolozane/Tazobactam; Metronidazole; Meropenem; Placebo
Intervention description: Ceftolozane 1000 mg / tazobactam 500 mg by IV infusion every 8 hours for 4 to 14 days. Participants with CrCL of 30 to ≤ 50 mL/min will receive ceftolozane 500 mg / tazobactam 250 mg.; Metronidazole 500 mg by IV infusion every 8 hours for 4 to 14 days.; Meropenem 1000 mg by IV infusion every 8 hours for 4 to 14 days. Participants with CrCL of 30 to ≤ 50 mL/min will receive IV infusion every 12 hours.; Saline by IV infusion every 8 hours for 4 to 14 days.
Intervention MeSH terms: Metronidazole; Meropenem; Tazobactam; Ceftolozane; Ceftolozane, tazobactam drug combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 268.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      This study aims to evaluate the efficacy of ceftolozane/tazobactam (MK-7625A) plus
      metronidazole versus meropenem in adults diagnosed with complicated intra-abdominal infection
      (cIAI). The primary hypothesis is ceftolozane/tazobactam plus metronidazole is non-inferior
      to meropenem, as measured by the clinical response rate at the Test-of Cure (TOC) visit in
      the Clinically Evaluable (CE) population.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Must have one of the following diagnoses in which there is evidence of bacterial
             intraperitoneal infection: Cholecystitis (including gangrenous cholecystitis) with
             rupture, perforation, or progression of the infection beyond the gallbladder wall;
             Acute gastric or small intestine including duodenal perforation, only if operated on >
             24 hours after perforation occurs; Traumatic perforation of the intestine (including
             colon), only if operated on > 12 hours after perforation occurs; Appendiceal
             perforation or peri-appendiceal abscess; Diverticular disease with perforation or
             abscess; Peritonitis due to other perforated viscus or following a prior operative
             procedure; Intra-abdominal abscess (including liver or spleen).

          -  Evidence of systemic infection

          -  Requires surgical intervention (e.g., laparotomy, laparoscopic surgery, or
             percutaneous draining of an abscess) within 24 hours of (before or after) the first
             dose of study drug

          -  If participant is to be enrolled preoperatively, the participant should have
             radiographic evidence of gastric or bowel perforation or intra-abdominal abscess or
             other radiographic evidence for cIAI

          -  Participants who failed prior antibacterial treatment for the current cIAI can be
             enrolled but must: (a) have a positive culture (from an intra-abdominal site or blood
             sample) and (b) require surgical intervention.

          -  Is a Chinese participant, defined as a person of Chinese descent. A potential
             participant who is of ex-China descent (e.g. Western European) descent living in China
             will be excluded

          -  Male agrees to use contraception during the treatment period, and for at least 30 days
             after the last dose of study medication, and refrain from donating sperm during this
             period

          -  Female is not pregnant or breastfeeding; is not a woman of childbearing potential
             (WOCBP); or if WOCBP agrees to use a contraceptive method that is highly effective, or
             be abstinent from heterosexual intercourse as their preferred and usual lifestyle
             during the treatment period, and for at least 30 days after the last dose of study
             medication; or must have a negative highly sensitive pregnancy test (serum) within 48
             hours before the first dose of study intervention.

        Exclusion Criteria:

          -  Has any of the following diagnoses: simple appendicitis; abdominal wall abscess; small
             bowel obstruction or ischemic bowel disease without perforation; spontaneous (primary)
             bacterial peritonitis associated with cirrhosis and chronic ascites; or pelvic
             infections

          -  Has any of the following diseases: acute suppurative cholangitis; infected necrotizing
             pancreatitis; pancreatic abscess

          -  Has complicated intra-abdominal infection managed by staged abdominal repair (STAR),
             open abdomen technique (i.e. fascia not closed) including temporary closure of the
             abdomen, or any situation where infection source control was not likely to be achieved

          -  Has abscess that is confirmed on imaging test but has not been or cannot be managed by
             surgical intervention including drainage

          -  Is expected to be cured by only surgical intervention (e.g., drainage) without use of
             systemic antibiotic therapy

          -  Has the following underlying conditions or the following serious conditions:
             considered unlikely to survive during the study period (predicted life expectancy is <
             4 weeks after randomization); organic brain or spinal cord disease; any
             rapidly-progressing disease or immediately life-threatening illness (including
             respiratory failure and septic shock); an immunocompromising condition

          -  Has a history of any hypersensitivity or allergic reaction to any beta-lactam,
             antibacterials, including cephalosporins, carbapenems, penicillins, or tazobactam, or
             metronidazole, or nitroimidazole derivatives; or if a skin test is required by local
             clinical regulations, has a positive skin test result if no prior history of allergic
             reaction to beta-lactam antibacterials

          -  A WOCBP who has a positive serum pregnancy test within 24 hours before the first dose
             of study intervention

          -  Used systemic antibiotic therapy with known coverage of pathogens that cause IAI for
             more than 24 hours during the previous 72 hours prior to the first dose of study drug,
             unless there is a documented treatment failure with such therapy

          -  For participants that are enrolled postoperatively, more than 1 dose of an active
             non-study antibacterial regimen administered postoperatively. For participants
             enrolled preoperatively, no postoperative non-study antibacterial therapy is allowed

          -  Participants who need additional non-study systemic antibacterial therapy with
             gram-negative activity in addition to study drug therapy; drugs with only
             gram-positive activity (eg, IV vancomycin, teicoplanin, linezolid and daptomycin) are
             allowed

          -  Anticipates treatment with traditional Chinese medicine or herbal medicine during
             study period

          -  Has received disulfiram, valproic acid or divalproex sodium within 14 days before the
             proposed first day of study drug or who are currently receiving probenecid

          -  Is currently participating in, or has participated in, any other clinical study
             involving the administration of investigational or experimental medication (not
             licensed by regulatory agencies) at the time of the presentation or during the
             previous 90 days prior to screening or is anticipated to participate in such a
             clinical study during the course of this study

          -  Has participated in a ceftolozane/tazobactam clinical study at any time in the past

          -  Has severe impairment of renal function (CrCL <30 mL/min) or requirement for
             peritoneal dialysis, hemodialysis or hemofiltration, or oliguria