A Clinical Trial for the Treatment of Carbapenem Resistant Gram-negative Bacterial Infection With Colistimethate Sodium for Injection

Inclusion Criteria:

• Age ≥ 18 years old (based on the signing time of the informed consent form).
• The subject (or their guardian) voluntarily signs an informed consent form.
• Clinical diagnosis confirmed carbapenem resistant Gram negative bacterial infections,including hospital-acquired bacterial pneumonia (HAP) / ventilator-associatedbacterial pneumonia (VAP), complicated urinary tract infection (cUTI) , complicatedintra-abdominal infection (cIAI), and bloodstream infection (BSI) subjects (minimumdisease criteria refer to each additional inclusion criteria)
• Cultivate a Gram negative bacterium identified as carbapenem resistant within 5 daysbefore or during the screening period (mainly including carbapenem resistantEnterobacteriaceae, carbapenem resistant Acinetobacter baumannii, and carbapenemresistant Pseudomonas aeruginosa), and the Gram negative bacteria showed drugresistance to carbapenems in vitro drug sensitive test. In this study, gram-negativebacteria resistant to carbapenems also included strains with bacterial drugsensitivity displayed as "intermediate", that is, resistant bacteria include strainsthat are intermediate and resistant to carbapenem antibiotics.
• Within 72 hours before randomization, for those who have previously received empiricalantimicrobial treatment, the duration of antimicrobial treatment (excluding polymyxinantibiotics) does not exceed 24 hours or the treatment exceed 48 hours but theinfection symptoms/signs still exist or become worsen.
• HAP/VAP subjects are required to meet:

1. Patients with acute pulmonary parenchymal infection who have been hospitalizedfor more than 48 hours or discharged for less than 7 days, or have receivedmechanical ventilation through oral or nasal tracheal intubation for at least 48hours;
2. Chest X-ray examination (or computed tomography) obtained within 72 hours beforerandomization shows new infiltrating lesions or progression of existing lesions;
3. Individuals with at least 2 of the following clinical symptoms/signs:
4. New occurrence cough；
5. Produce purulent sputum or tracheal secretions；
6. The auscultation results are accord with pneumonia/lung consolidation (suchas wet rale, dry rale, bronchial breath sound, egophony, dull percussionnote);
7. Difficulty in breathing, shortness of breath (respiratory rate>25breaths/minute), or hypoxemia (oxygen saturation< 90% when breathing indoorair at standard atmospheric pressure or arterial blood oxygen partialpressure (PaO2) obtained through arterial blood gas (ABG)<60 mmHg);
8. The oxygenation index (arterial partial pressure of oxygen/percentage ofinhaled oxygen concentration (PaO2/FiO2)) deteriorates, requiring urgentchanges in ventilator support status or changes in positive end expiratorypressure ventilation volume.
9. Within 72 hours before the first dose of study drug, the subject is required totake appropriate respiratory specimens (such as sputum, respiratory secretions,culture samples, etc.)
10. With at least one of the following evidence of systemic inflammatory reactions:
11. Recorded fever (oral temperature ≥ 38 ℃ or axillary temperature ≥ 37.5 ℃) orhypothermia (rectal/core temperature ≤ 35 °C);

≥ 10000/mm ^3 or peripheral blood leukocytecount ≤ 4500/mm ^3 or peripheral blood rod-shaped granulocytes >15%.

• CUTI subjects with/without pyelonephritis are required to meet:

1. Urinary routine examination shows pyuria, i.e. non centrifuge urine examination ≥ 10 WBC/µ l, centrifuge urine examination white blood cell count (WBC) >5/HPF, orurine routine WBC higher than the upper limit of normal values of eachparticipating unit;
2. Individuals with at least 2 of the following clinical symptoms or signs:
3. Fever with or without chills or chills. Acute pyelonephritis must have signsof fever.
4. Lateral abdominal pain or pelvic pain;
5. Nausea or vomiting;
6. Difficulty of urinating, frequent urination, urgency or pain in urination;
7. There is tenderness or percussion pain in the costovertebral angle duringphysical examination.
8. The subject must have at least one of the following basic diseases or conditionswith abnormal urinary tract structure or function(excluding acutepyelonephritis):
9. Urinary tract obstruction (renal stones, renal fibrosis);
10. Functional/anatomical abnormalities of the genitourinary tract (includinganatomical abnormalities or neurogenic bladder) or residual urine volumeafter urination ≥ 100 mL;
11. Urinary retention, including those caused by benign prostatic hypertrophy;
12. Patients with renal diseases such as glomerulonephritis and nephroticsyndrome;
13. It is known that patients meet the requirements of 30 mg/g<urinarymicroalbumin/creatinine ratio ≤ 300 mg/g with diabetes nephropathy.
14. Within 72 hours before the first dose of study drug, subjects are required totake clean mid section urine, with a bacterial colony count in urine culturegreater than 105 CFU/mL.

• CIAI subjects are required to meet:

1. Subjects must arrange or have completed open surgery, laparoscopic surgery, orpercutaneous drainage of abdominal abscesses for the diagnosis and treatment ofcIAI within 24 hours of enrollment or within 24 hours of administering the firstdose of antibiotics;
2. For subjects enrolled before surgery, study medication can only be administeredwhen there is a high suspicion or diagnosis of intra-abdominal infection, andbaseline intra-abdominal culture specimens from the infected site are planned tobe obtained;
3. Appearance of one or more systemic symptoms or signs of cIAI, such as fever,hypotension, abdominal pain, nausea and vomiting, abdominal lumps found duringphysical examination, and changes in mental state.
4. With at least one of the following evidence of systemic inflammatory response:
5. Recorded fever (oral temperature ≥ 38 ℃ or axillary temperature ≥ 37.5 ℃) orhypothermia (rectal/core temperature ≤ 35 °C);
6. Peripheral blood leukocyte count ≥ 10000 /mm^3 or peripheral blood leukocytecount ≤ 4500 /mm^3 or peripheral blood rod-shaped granulocytes >15%.

• BSI subjects are required to meet:

1. At least one of blood culture tests conducted was positive within 5 days prior toscreening, indicating the presence of Gram negative bacteria. This research caninclude participants with multiple microbial(Including carbapenem resistant Gramnegative bacteria) infections. (Note: This study plans to include patients withprimary BSI, defined as pathogenic microorganisms with positive blood culturethat are not associated with other infection sites.)
2. With at least one of the following evidence of systemic inflammatory response:
3. Recorded fever (oral temperature ≥ 38 ℃ or axillary temperature ≥ 37.5 ℃) orhypothermia (rectal/core temperature ≤ 35 °C)；
4. Peripheral blood leukocyte count ≥ 10000 /mm^3 or peripheral blood leukocytecount ≤ 4500 /mm^3 or peripheral blood rod-shaped granulocytes >15%.

Exclusion Criteria:

• Individuals who currently have epilepsy/myasthenia gravis or have a history ofseizures (excluding febrile seizures in childhood)/myasthenia gravis history.
• Individuals undergoing hemodialysis or peritoneal dialysis.
• Invasive aspergillosis, mucormycosis, or other invasive fungal diseases.
• Current patients complicated with other infections, including endocarditis,osteomyelitis, central nervous system infection (such as meningitis, brain abscess,infection after cerebrospinal fluid shunt or shunt device infection), artificial jointinfection, and active tuberculosis.
• It is currently complicated with refractory septic shock, and there was stillpersistent hypotension after sufficient fluid resuscitation or pressure therapy beforerandomization.
• Evidence of obvious liver disease or dysfunction, including known acute viralhepatitis or hepatic encephalopathy.
• Individuals with immunodeficiency or low immune function, including but not limitedto: human immunodeficiency virus infection, hematological malignancies, bone marrowtransplantation, immunosuppressive therapy, systemic corticosteroid therapy (definedas a daily dose equivalent to prednisone ≥ 20 mg and a course of treatment>14 days).
• Individuals with any laboratory test abnormalities during the screening period:aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) are 5 timeshigher than the upper limit of normal, or AST and/or ALT are 3 times higher than theupper limit of normal and total bilirubin is 1.5 times higher than the upper limit ofnormal, or neutrophil count is less than 1.0× 10^9/L or platelet count<60 ×10^9/L;Creatinine clearance rate ≤ 50 ml/min.
• According to the clinical judgment of the researchers, the expected survival period isless than 1 month.
• Individuals with allergic reactions to polymyxin or carbapenems.
• Subjects who require more than 2 systemic antibiotics for the treatment of Gramnegative bacterial infections.
• Patients with acute physiology and chronic health (APACHE II) scores greater than 30.
• HAP/VAP subjects need to exclude:

1. Patients with lung diseases that can interfere with treatment responseevaluation, (such as cystic fibrosis, granulomatous diseases, pulmonary fungalinfections, or recent pulmonary embolism);
2. Individuals with lung abscess, empyema, or obstructive pneumonia;
3. New York Heart Association (NYHA) Grade III-IV heart failure
4. Lung or heart transplant recipients.

• CUTI subjects with/without pyelonephritis need to excluded:

1. Subjects suspected or confirmed to have prostatitis;
2. Renal transplant recipients;
3. Individuals with ileal loops;
4. Individuals who may continue to receive prophylactic treatment with antibioticsduring clinical trials, such as those with bladder ureteral reflux;
5. Patients that the indwelling catheter cannot be replaced during the study;
6. Any unrecovered pelvic or urinary tract trauma;
7. Individuals with simple urinary tract infections.

• cIAI subjects need to exclude:

1. Upper gastrointestinal perforation, unless there is clear evidence of secondaryinfection in the abdominal cavity;
2. Enrolled after surgery, but received over 1 dose of potentially effectivesystemic antibacterial medication before surgery.

• BSI subjects need to exclude:

1. Subjects who only obtain positive blood culture through venous catheters (if bothperipheral venous puncture blood culture and venous catheter blood culture showthe same microbiological results, subjects can be selected);
2. Infection is caused by intravascular sources, such as endocarditis, infectedvascular grafts, and permanent intravascular devices that cannot be removedduring treatment.