Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria
Condition: Serious Bacterial Infection
MeSH terms: Infections; Communicable Diseases; Bacterial Infections
Intervention: ATM-AVI; BAT
Intervention description: ATM-AVI doses (loading, extended loading and maintenance) and the dosing frequency of the maintenance dose are dependent on renal function. Subjects will be given a loading dose of 500 mg ATM plus 167 mg AVI or 675 mg ATM plus 225 mg AVI over a period of 30 minutes. This treatment will immediately be followed by an extended loading dose of 1500 mg ATM plus 500 mg AVI or 675 mg ATM plus 225 mg AVI over a period of 3 hours. Then there will be a 3 hour or 5 hour gap. Subjects will receive a maintenance dose of 1500 mg ATM plus 500 mg AVI every 6 hours or 750 mg ATM plus 250 mg AVI every 6 hours, or 675 mg ATM plus 225 mg AVI every 8 hours. Subjects with cIAI will also receive Metronidazole (MTZ) 500 mg IV q8h over 60 minutes. The first dose of MTZ will be started immediately after the extended loading dose of ATM-AVI has completed and treatment will be continued until the end of the treatment period.; The comparator treatment in this study is best available therapy (BAT) based upon site practice and local epidemiology. The choice of BAT (monotherapy or combination) for each subject must be recorded prior to randomization. If the chosen BAT does not provide adequate anaerobic coverage for cIAI subjects MTZ is to be administered as a co therapy. BAT dose, frequency, dose adjustments with renal impairment will be based on per local package inserts.
Intervention MeSH terms: Aztreonam; Avibactam
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Serious bacterial infection; cIAI; HAP/(VAP; cUTI; BSI; MBL

Summary:

      Phase 3 study to determine the efficacy, safety, and tolerability of aztreonam- avibactam
      (ATM- AVI) versus best available therapy (BAT) in the treatment of hospitalized adults with
      complicated intra-abdominal infections (cIAI), nosocomial pneumonia (NP) including hospital
      acquired pneumonia (HAP) and ventilator associated pneumonia (VAP), complicated urinary tract
      infections (cUTI), or bloodstream infections (BSI) due to metallo-β-lactamase (MBL)-
      producing Gram-negative bacteria.
    

Eligibility criteria:

        Inclusion Criteria All Subjects

          1. Subject must be ≥18 years of age.

          2. Evidence of a personally signed and dated informed consent document indicating that
             the subject or a legally acceptable representative has been informed of all pertinent
             aspects of the study.

          3. Subjects must have a confirmed diagnosis of serious bacterial infection, specifically
             cIAI, HAP/VAP, cUTI, or BSI requiring administration of IV antibacterial therapy.

          4. Subjects must have an MBL- positive Gram- negative bacteria (an Enterobacteriaceae
             and/or Stenotrophomonas maltophilia for which the imipenem or meropenem MIC is ≥ 4
             µg/mL), that was isolated from an appropriate specimen obtained within 7 days prior to
             screening.

          5. Female subject of childbearing potential must have a negative serum or urine pregnancy
             test, with sensitivity of at least 25 mIU/mL.

          6. Subjects who have received more than 48 hours of an appropriate prior systemic
             antibiotic[s] for a carbapenem non -susceptible pathogen may be enrolled if they
             demonstrate worsening or lack of improvement of objective symptoms or signs of
             infection (Note: antibiotic[s] is considered appropriate if microbiological
             susceptibility test results show that all carbapenem non -susceptible pathogens are
             susceptible to the systemic antibiotic[s] received).

        Additional Inclusion Criteria- cIAI Subjects

          1. Subject must have a specimen obtained from an abdominal source during a surgical
             intervention within 7 days prior to screening from which a study qualifying pathogen
             was isolated upon culture. Surgical intervention includes open laparotomy,
             percutaneous drainage of an abscess, or laparoscopic surgery.

          2. The subject has at least 1 of the following diagnosed during the surgical
             intervention:

             • Cholecystitis with gangrenous rupture or perforation or progression of the infection
             beyond the gallbladder wall;

             • Diverticular disease with perforation or abscess;

               -  Appendiceal perforation or peri-appendiceal abscess;

               -  Acute gastric or duodenal perforations, only if operated on >24 hours after
                  diagnosis;

               -  Traumatic perforation of the intestines, only if operated on >12 hours after
                  diagnosis;

               -  Other secondary peritonitis (not primary/ spontaneous bacterial peritonitis
                  associated with cirrhosis or chronic ascites);

               -  Intra abdominal abscess (including of the liver and spleen provided that there is
                  extension beyond the organ with evidence of intra peritoneal involvement).

          3. Subject has at least 1 of the following signs / symptoms from each of the following 2
             groups:

             • Group A: Evidence of systemic inflammatory response:

             • Documented fever (defined as body temperature ≥38°C) or hypothermia (with a rectal
             core body temperature ≤35°C);

             • Elevated white blood cells (WBC) (>12000 cells/µL);

             • Systolic blood pressure (SBP) <90 mmHg or mean arterial pressure (MAP) <70 mmHg, or
             a SBP decrease of >40 mmHg;

             • Increased heart rate ( >90 beats per minute [bpm]) and respiratory rate (>20
             breaths/min);

             • Hypoxemia (defined as oxygen [O2] saturation <95% by pulse oximetry);

             • Altered mental status.

             • Group B: Physical findings consistent with intra abdominal infection, such as:

             • Abdominal pain and/or tenderness, with or without rebound;

             • Localized or diffuse abdominal wall rigidity;

             • Abdominal mass.

        Additional Inclusion Criteria - HAP/VAP Subjects

          1. Onset of symptoms >48 hours after admission or <7 days after discharge from an
             inpatient care facility (for which the duration of admission was >3 days).

          2. New or worsening infiltrate on chest X- ray (or computerized tomography [CT]- scan)
             obtained within 48 hours prior to randomization.

          3. At least 1 of the following:

               -  Documented fever (temperature ≥38°C) or hypothermia (rectal/core temperature
                  ≤35°C);

               -  WBC ≥10,000 cells/mm3, leukopenia with total WBC ≤4500 cells/mm3, or >15%
                  immature neutrophils (bands) noted on peripheral blood smear.

          4. At least 2 of the following:

             • A new cough (or worsening of cough at Baseline);

             • Production of purulent sputum or purulent endotracheal secretions;

             • Auscultatory finding consistent with pneumonia/pulmonary consolidation (eg, rales,
             rhonchi, bronchial breath sounds, dullness on percussion, egophony);

             • Dyspnea, tachypnea, or hypoxemia (O2 saturation <90% or partial pressure of O2
             [pO2]<60 mmHg while breathing room air);

             • Need for acute changes in the ventilator support status/system to enhance
             oxygenation, as determined by worsening oxygenation (arterial blood gas [ABG] or pO2
             in arterial blood [PaO2]/fraction of inspired O2 [FiO2]) or needed changes in the
             amount of positive end expiratory pressure.

          5. Subjects must have a respiratory specimen obtained within 7 days prior to screening
             for Gram stain and culture from which a study qualifying pathogen was isolated upon
             culture. This includes culture of either an expectorated sputum or a specimen of
             respiratory secretions obtained by endotracheal aspiration in intubated subjects, or
             by bronchoscopy with bronchoalveolar lavage (BAL), mini BAL or protected specimen
             brush (PSB) sampling.

        Additional Inclusion Criteria - cUTI Subjects

          1. Subject had urine within 7 days prior to screening that cultured positive; containing
             ≥10^5 colony forming unit (CFU)/mL of at least 1 carbapenem non susceptible, MBL
             positive Gram-negative bacteria, ie, the isolate from the study qualifying culture.

          2. Subject had pyuria in the 7 days prior to screening as determined by a midstream clean
             catch or catheterized urine specimen with ≥10 white blood cells (WBCs) per HighPower
             Field (HPF) on standard examination of urine sediment or ≥10 WBCs/mm3 in unspun urine.

          3. Subject demonstrates either acute pyelonephritis or complicated lower UTI without
             pyelonephritis as defined by the following criteria:

             a. Acute pyelonephritis indicated by flank pain (which must have onset or worsened
             within 7 days of enrollment) or costovertebral angle tenderness on examination and at
             least 1 of the following: i) Fever, defined as body temperature ≥38°C (with or without
             patient symptoms of rigor, chills, or warmth); ii) Nausea and/or vomiting. OR b.
             Complicated lower UTI, as indicated by qualifying symptoms plus at least 1
             complicating factor as follows: i) Qualifying symptoms: subject must have at least 2
             of the following symptoms with at least 1 symptom from Group A:

             • Group A symptoms include dysuria, urgency, frequency, and or suprapubic pain;

             • Group B symptoms include fever (defined as body temperature ≥38°C with or without
             patient symptoms of rigor, chills, warmth), nausea, and/or vomiting.

             ii) Complicating factors: subject must have at least 1 of the following complicating
             factors:

             • Documented history of urinary retention (male subjects);

             • Obstructive uropathy that is scheduled to be medically or surgically relieved during
             study therapy and before the EOT;

             • Functional or anatomical abnormality of the urogenital tract, including anatomic
             malformations or neurogenic bladder, or with a postvoid residual urine volume of at
             least 100 mL;

             • Use of intermittent bladder catheterization or presence of an indwelling bladder
             catheter for at least 48 hours;

             • Urogenital procedure (such as cystoscopy or urogenital surgery) within the 7 days
             prior to obtainment of the specimen used for the study qualifying culture.

             Additional Inclusion Criteria - BSI Subjects

          1. Subject has a confirmed diagnosis of primary BSI or catheter related BSI (CR- BSI).

          2. Signs and symptoms of systemic infection characterized by at least one of the
             following:

               1. Chills, rigors, or fever (temperature of ≥38.0°C or ≥100.4°F);

               2. Elevated white blood cell count (≥10,000/mm3) or left shift (>15% immature
                  polymorphonuclear leukocytes (PMNs)).

        Exclusion Criteria All Subjects

          1. History of serious allergic reaction (anaphylaxis, angioedema, bronchospasm,
             hypersensitivity) to any systemic antibacterial allowed per protocol.

          2. Subject has a concurrent infection that may interfere with the evaluation of response
             to the study antibiotics.

          3. Subject has a need for effective concomitant systemic antibacterials in addition to
             those allowed per protocol for the diagnoses under study.

          4. Estimated CrCL ≤15 mL/min or anticipated requirement for dialysis during the study.

        Additional Exclusion Criteria - cIAI Subjects

          1. Subject has infections limited to the hollow viscous, such as simple cholecystitis,
             gangrenous cholecystitis without rupture, and simple appendicitis, or has acute
             suppurative cholangitis, infected necrotizing pancreatitis, or pancreatic abscess.

          2. Subject has abdominal wall abscess or small bowel obstruction without perforation or
             ischemic bowel without perforation.

          3. Subject has a cIAI managed by staged abdominal repair (STAR), or "open abdomen"
             technique, or marsupialization. This criterion is intended to exclude subjects in whom
             the abdomen is left open, particularly those for whom re operation is planned.

        Additional exclusion criteria - cUTI Subjects 1. Subjects with suspected or confirmed
        complete obstruction of any portion of the urinary tract, perinephric or intrarenal
        abscess, or prostatitis, or history of any illness that, in the opinion of the
        investigator, may confound the results of the study or pose additional risk in
        administering the study therapy to the subject.

        2. Any recent history of trauma to the pelvis or urinary tract.

        Additional exclusion criteria - BSI Subjects

        1. Subject has a prosthetic cardiac valve or synthetic endovascular graft. 2. Subject has a
        suspected or documented medical condition with well-defined requirement for prolonged
        antibiotic treatment (eg, infectious endocarditis, osteomyelitis/septic arthritis,
        undrainable/undrained abscess, unremoveable/unremoved prosthetic associated infection).