. 2019 Nov 21;12:3607–3623. doi: 10.2147/IDR.S225553

Table 1.

CREDIBLE-CR Study Inclusion And Exclusion Criteria By Clinical Diagnosis

	HAP/VAP/HCAP	BSI/Sepsis	cUTI
Definition	HAP is defined as an acute bacterial pneumonia in a patient hospitalized for ≥48 hrs or developing pneumonia within 7 days following discharge from a hospital. Patients may suffer from acute respiratory failure and require mechanical ventilation (ventilated-HAP). VAP is defined as acute bacterial pneumonia in a patient who is already receiving mechanical ventilation for ≥48 hrs. HCAP is defined as an acute bacterial pneumonia in a patient who required hospitalization in an acute care hospital for ≥48 hrs within 90 days prior to current infection; or resided in a nursing home or long-term care facility; or received IV antibiotic treatment, chemotherapy, or wound care; or attended hemodialysis clinic within 30 days prior to current infection.	The BSI/sepsis category includes bacteremia or sepsis caused by infections other than HAP/VAP/HCAP or cUTI. Documented BSI caused by a CR Gram-negative pathogen. Systemic response to infection, meeting the clinical criteria of SIRS and an identified infection source (eg, severe skin infection, intra-abdominal infection) caused by a CR Gram-negative pathogen.	cUTI is defined as a clinical syndrome characterized by pyuria and a documented microbial pathogen on urine culture, accompanied by local and systemic signs and symptoms including fever, chills, malaise, flank pain, back pain, and/or costovertebral angle pain or tenderness that occur in the presence of a functional or anatomical abnormality of the urinary tract or in the presence of catheterization and requiring hospitalization for the parenteral (IV) treatment of cUTI.
Inclusion criteria	All patients must have at least one of the following clinical features: New onset or worsening of pulmonary symptoms or signs, such as cough, dyspnea, tachypnea (eg, respiratory rate >25 breaths/minute), expectorated sputum production, or requirement for mechanical ventilation Hypoxemia (eg, a partial pressure of oxygen <60 mmHg while the patient is breathing room air, as determined by ABG or worsening of the ratio of the partial pressure of oxygen to the fraction of inspired oxygen [PaO₂/FiO₂]) Need for acute changes in the ventilator support system to enhance oxygenation, as determined by worsening oxygenation (ABG or PaO₂/FiO₂) or needed changes in the amount of positive end-expiratory pressure New onset of or increase in (quantity or characteristics) suctioned respiratory secretions demonstrating evidence of inflammation and absence of contamination All patients must have at least one of the following signs: Documented fever (eg, core body temperature [tympanic, rectal, esophageal] ≥38°C [100.4°F], oral temperature ≥37.5°C or axillary temperature ≥37°C) Hypothermia (eg, core body temperature [tympanic, rectal, esophageal] ≤35°C [95°F], oral temperature ≤35.5°C or axillary temperature ≤36°C) Leukocytosis with a total peripheral WBC count ≥10,000 cells/mm³ Leukopenia with total peripheral WBC count ≤4500 cells/mm³ >15% immature neutrophils (bands) noted on peripheral blood smear All patients must have a chest radiograph or lung CT scan within 48 hrs prior to randomization showing the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia.	BSI-specific inclusion criteria: Patients who have one or more positive blood cultures identifying a CR Gram-negative pathogen that is consistent with the patient’s clinical condition Patients who have signs or symptoms associated with bacteremia Sepsis-specific inclusion criteria Patients defined for SIRS, indicated by having two or more of the following responses: Oral or tympanic body temperature >38°C (100.4°F) or <36°C (96.8°F) Tachycardia, heart rate >90 beats/minute Tachypnea, manifested by a respiratory rate >20 breaths/minute or hyperventilation, as indicated by an arterial partial pressure of carbon dioxide (PaCO₂) of <32 mmHg WBC >12,000 cells/mm³, <4000 cells/mm³, or >10% immature (band) forms Patients with an identified infection site from which a CR Gram-negative pathogen has been isolated using an appropriate clinical specimen	All patients must have a cUTI with a history of at least one of the following: Indwelling urinary catheter or recent instrumentation of the urinary tract (within 14 days prior to Screening) Urinary retention caused by benign prostatic hypertrophy Urinary retention of ≥100 mL or more of residual urine after voiding (neurogenic bladder) Obstructive uropathy (nephrolithiasis, fibrosis, etc.) Azotemia caused by intrinsic renal disease (BUN and creatinine values greater than normal clinical laboratory values) All patients must have at least two of the following signs or symptoms: Chills, rigors, or warmth associated with fever (body temperature ≥38°C [100.4°F]) Flank pain (pyelonephritis) or suprapubic/pelvic pain (cUTI) Nausea or vomiting Dysuria, urinary frequency, or urinary urgency Costovertebral angle tenderness on physical examination All patients must have evidence of pyuria on urinalysis demonstrated by: Dipstick analysis positive for leukocyte esterase or ≥10 WBCs/μL in unspun urine, or ≥10 WBCs/high power field in spun urine Patients who had a positive urine culture within 48 hrs prior to randomization containing ≥10⁵ CFU/mL of a CR Gram-negative uropathogen are eligible for this study. (Note: patients may be randomized prior to the results of the urine culture if they have evidence of a CR pathogen.) Patients receiving antibiotic prophylaxis for cUTI who present with signs and symptoms consistent with an active new cUTI may be enrolled provided all other eligibility criteria are met including obtaining a pre-treatment qualifying urine culture.
Exclusion criteria	Patients who meet any of the following criteria at Screening will be excluded from the study: Patients who have known or suspected community-acquired bacterial pneumonia, atypical pneumonia, viral pneumonia or chemical pneumonia (including aspiration of gastric contents, inhalation injury) Patients receiving concomitant aerosolized antibiotics with Gram-negative activity	BSI-specific exclusion criteria Patients who meet any of the following criteria at Screening will be excluded from the study: Patients who have a positive blood culture only obtained from an IV catheter. If both peripheral venipuncture blood culture and IV catheter blood culture show the same organism, the patient is eligible Patients with BSI considered to be due to an endovascular source, eg, endocarditis, infected vascular graft, a permanent intravascular device that cannot be removed during the course of treatment Sepsis-specific exclusion criteria Patients who meet any of the following criteria at Screening will be excluded from the study: Patients who do not have an identified source of a bacterial infection and an identified CR Gram-negative pathogen Patients who have an alternative explanation for the physiological parameters of SIRS, eg, cardiogenic shock, cardiac arrhythmia, or hyperthyroid storm Patients who have infections where isolation of a Gram-negative pathogen is unlikely to be causing the infection, such as that in the upper respiratory system, head and neck, pelvic or genital organ, etc.	Patients who meet any of the following criteria at Screening will be excluded from the study: Patients whose urine culture at study entry isolates more than two uropathogens, regardless of colony count, or patients with a confirmed fungal cUTI Patients with asymptomatic bacteriuria, the presence of >10⁵ CFU/mL of a uropathogen and pyuria but without local or systemic symptoms Patients with an ileal loop for urine outflow (patients with BSI/sepsis and an ileal loop are eligible) Patients with acute uncomplicated pyelonephritis, ie, absence of anatomic urinary tract abnormality Patients with vesico-ureteric reflux

HAP/VAP/HCAP

BSI/Sepsis

cUTI

Definition

HAP is defined as an acute bacterial pneumonia in a patient hospitalized for ≥48 hrs or developing pneumonia within 7 days following discharge from a hospital. Patients may suffer from acute respiratory failure and require mechanical ventilation (ventilated-HAP).
VAP is defined as acute bacterial pneumonia in a patient who is already receiving mechanical ventilation for ≥48 hrs.
HCAP is defined as an acute bacterial pneumonia in a patient who required hospitalization in an acute care hospital for ≥48 hrs within 90 days prior to current infection; or resided in a nursing home or long-term care facility; or received IV antibiotic treatment, chemotherapy, or wound care; or attended hemodialysis clinic within 30 days prior to current infection.

The BSI/sepsis category includes bacteremia or sepsis caused by infections other than HAP/VAP/HCAP or cUTI.
Documented BSI caused by a CR Gram-negative pathogen.
Systemic response to infection, meeting the clinical criteria of SIRS and an identified infection source (eg, severe skin infection, intra-abdominal infection) caused by a CR Gram-negative pathogen.

cUTI is defined as a clinical syndrome characterized by pyuria and a documented microbial pathogen on urine culture, accompanied by local and systemic signs and symptoms including fever, chills, malaise, flank pain, back pain, and/or costovertebral angle pain or tenderness that occur in the presence of a functional or anatomical abnormality of the urinary tract or in the presence of catheterization and requiring hospitalization for the parenteral (IV) treatment of cUTI.

Inclusion criteria

All patients must have at least one of the following clinical features:

New onset or worsening of pulmonary symptoms or signs, such as cough, dyspnea, tachypnea (eg, respiratory rate >25 breaths/minute), expectorated sputum production, or requirement for mechanical ventilation
Hypoxemia (eg, a partial pressure of oxygen <60 mmHg while the patient is breathing room air, as determined by ABG or worsening of the ratio of the partial pressure of oxygen to the fraction of inspired oxygen [PaO₂/FiO₂])
Need for acute changes in the ventilator support system to enhance oxygenation, as determined by worsening oxygenation (ABG or PaO₂/FiO₂) or needed changes in the amount of positive end-expiratory pressure
New onset of or increase in (quantity or characteristics) suctioned respiratory secretions demonstrating evidence of inflammation and absence of contamination

All patients must have at least one of the following signs:

Documented fever (eg, core body temperature [tympanic, rectal, esophageal] ≥38°C [100.4°F], oral temperature ≥37.5°C or axillary temperature ≥37°C)
Hypothermia (eg, core body temperature [tympanic, rectal, esophageal] ≤35°C [95°F], oral temperature ≤35.5°C or axillary temperature ≤36°C)
Leukocytosis with a total peripheral WBC count ≥10,000 cells/mm³
Leukopenia with total peripheral WBC count ≤4500 cells/mm³
>15% immature neutrophils (bands) noted on peripheral blood smear

All patients must have a chest radiograph or lung CT scan within 48 hrs prior to randomization showing the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia.

BSI-specific inclusion criteria:

Patients who have one or more positive blood cultures identifying a CR Gram-negative pathogen that is consistent with the patient’s clinical condition
Patients who have signs or symptoms associated with bacteremia

Sepsis-specific inclusion criteria
Patients defined for SIRS, indicated by having two or more of the following responses:

Oral or tympanic body temperature >38°C (100.4°F) or <36°C (96.8°F)
Tachycardia, heart rate >90 beats/minute
Tachypnea, manifested by a respiratory rate >20 breaths/minute or hyperventilation, as indicated by an arterial partial pressure of carbon dioxide (PaCO₂) of <32 mmHg
WBC >12,000 cells/mm³, <4000 cells/mm³, or >10% immature (band) forms
Patients with an identified infection site from which a CR Gram-negative pathogen has been isolated using an appropriate clinical specimen

All patients must have a cUTI with a history of at least one of the following:

Indwelling urinary catheter or recent instrumentation of the urinary tract (within 14 days prior to Screening)
Urinary retention caused by benign prostatic hypertrophy
Urinary retention of ≥100 mL or more of residual urine after voiding (neurogenic bladder)
Obstructive uropathy (nephrolithiasis, fibrosis, etc.)
Azotemia caused by intrinsic renal disease (BUN and creatinine values greater than normal clinical laboratory values)

All patients must have at least two of the following signs or symptoms:

Chills, rigors, or warmth associated with fever (body temperature ≥38°C [100.4°F])
Flank pain (pyelonephritis) or suprapubic/pelvic pain (cUTI)
Nausea or vomiting
Dysuria, urinary frequency, or urinary urgency
Costovertebral angle tenderness on physical examination

All patients must have evidence of pyuria on urinalysis demonstrated by:

Dipstick analysis positive for leukocyte esterase or ≥10 WBCs/μL in unspun urine, or ≥10 WBCs/high power field in spun urine

Patients who had a positive urine culture within 48 hrs prior to randomization containing ≥10⁵ CFU/mL of a CR Gram-negative uropathogen are eligible for this study. (Note: patients may be randomized prior to the results of the urine culture if they have evidence of a CR pathogen.)
Patients receiving antibiotic prophylaxis for cUTI who present with signs and symptoms consistent with an active new cUTI may be enrolled provided all other eligibility criteria are met including obtaining a pre-treatment qualifying urine culture.

Exclusion criteria

Patients who meet any of the following criteria at Screening will be excluded from the study:

Patients who have known or suspected community-acquired bacterial pneumonia, atypical pneumonia, viral pneumonia or chemical pneumonia (including aspiration of gastric contents, inhalation injury)
Patients receiving concomitant aerosolized antibiotics with Gram-negative activity

BSI-specific exclusion criteria
Patients who meet any of the following criteria at Screening will be excluded from the study:

Patients who have a positive blood culture only obtained from an IV catheter. If both peripheral venipuncture blood culture and IV catheter blood culture show the same organism, the patient is eligible
Patients with BSI considered to be due to an endovascular source, eg, endocarditis, infected vascular graft, a permanent intravascular device that cannot be removed during the course of treatment

Sepsis-specific exclusion criteria
Patients who meet any of the following criteria at Screening will be excluded from the study:

Patients who do not have an identified source of a bacterial infection and an identified CR Gram-negative pathogen
Patients who have an alternative explanation for the physiological parameters of SIRS, eg, cardiogenic shock, cardiac arrhythmia, or hyperthyroid storm
Patients who have infections where isolation of a Gram-negative pathogen is unlikely to be causing the infection, such as that in the upper respiratory system, head and neck, pelvic or genital organ, etc.

Patients who meet any of the following criteria at Screening will be excluded from the study:

Patients whose urine culture at study entry isolates more than two uropathogens, regardless of colony count, or patients with a confirmed fungal cUTI
Patients with asymptomatic bacteriuria, the presence of >10⁵ CFU/mL of a uropathogen and pyuria but without local or systemic symptoms
Patients with an ileal loop for urine outflow (patients with BSI/sepsis and an ileal loop are eligible)
Patients with acute uncomplicated pyelonephritis, ie, absence of anatomic urinary tract abnormality
Patients with vesico-ureteric reflux

Abbreviations: HAP, hospital-acquired pneumonia; VAP, ventilator-associated pneumonia; HCAP, healthcare-associated pneumonia; BSI, bloodstream infection; cUTI, complicated urinary tract infection; CR, carbapenem-resistant; SIRS, systemic inflammatory response syndrome; IV, intravenous; ABG, arterial blood gas; BUN, blood urea nitrogen; WBC, white blood cell; CT, computed tomography; CFU, colony-forming unit.