Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria

Inclusion Criteria

• •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).
• •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.
• •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.
• •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.
• •<!-- -->
• •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)).