Safety and Efficacy Study of Ftortiazinon in the Treatment of Patients With Complicated Urinary Tract Infections Caused by P. Aeruginosa

Inclusion Criteria:

1. The ability to understand the requirements of the study participants, to givewritten consent to participate in the study (including the use and transfer ofinformation about the patient's health related to the study) and theimplementation of the procedures provided by the Study Protocol.

2. Availability of the patient's written consent to participate in the studyaccording to the current legislation.

3. Male or female participants must be ≥18 and ≤80 years of age. 4. It is expectedthat patient's treatment of complicated UTI will require hospitalization andthe use of antibiotic therapy.

4. Suspected or documented complicated UTI as defined below and subject to themandatory presence of one or more of the risks associated with the complicatedUTI listed below:

Complicated urinary tract infection (complicated UTI):

• presence of at least 2 of the following signs or symptoms:

• chills, tremors, or body temperature increases associated with fever (bodytemperature of 38ºC) (fever documented by a medical professional within 24 hoursprior to screening);

• nausea or vomiting within 24 hours prior to screening;

• dysuria, frequent urination or urgent need to urinate;

• pain in the lower abdomen;

• acute pain in the side (occurred within 7 days prior to randomization) or pain inthe region of the rib-vertebral angle during physical examination.

• leukocyturia in a urine sample (presence of at least one of the following signs):

• positive reaction to leukocyte esterase based on the results of the common urineexamination;

• number of leukocytes ≥ 10 cells/mm3 in non-centrifuged urine sample;

• number of leukocytes ≥ 10 cells / per HPF in the urine sediment. 6. At least one ofthe following associated risks: • periodic bladder catheterization or the presenceof a permanent bladder catheter, ureters (ureter stent), kidneys (nephrostoma) (catheters installed more than 24 hours prior to screening should be removed orreplaced prior to collection of an urine sample for analysis and sowing, unlessremoval or replacement is considered unsafe or contraindicated);

• presence of known functional or anatomical abnormalities in the urinary system,including malformations, neurogenic bladder, presence of residual urine volume ≥ 100 ml, stricture after surgery and/or malformations of the urinary tract,separate drainage of the kidney and/or bilateral nephrostomy tubes;

• complete or partial obstructive uropathy (e.g. nephrolithiasis, tumor,fibrosis, urethral stricture, cystolithiasis) that is expected to be subjectedto therapeutic or surgical treatment during treatment with the drug under study (until the end of therapy);

• azotemia defined as blood urea nitrogen level (BUN) > 20 mg/dl, blood urealevel > 42.8 mg/dl, or serum creatinine > 1.4 mg/dl due to known kidney diseasein anamnesis;

• chronic urinary retention in men, e.g. due to the previously diagnosed benignprostatic hypertrophy.

7. Obtaining the patient's initial urine sample for sowing within 24 hoursbefore randomization (patients can be randomized in this study and starttherapy with the drug under study before the results of the initial urineculture become known to the researcher).
8. A reasonable assumption that any installed urinary device (e.g.,nephrostomy catheter, permanent stents) will be surgically removed orreplaced before or within 24 hours of randomization (temporary cathetersthat were installed more than 24 hours before screening should be removedor replaced before urine sample collection for analysis and sowing).
9. Recurrent complicated urinary tract infection within 12 months before thestudy (presence of complicated urinary tract infection in anamnesis with afrequency of more than twice per year).
10. Suspected infection caused by multiresistant strains of P. aeruginosa,inefficiency of previous treatment.
11. High risk of complicated UTI caused by P. aeruginosa (e.g. pseudomonalcomplicated UTI in anamnesis, therapy of 20 mg or more with prednisone orequivalent steroid and other risk factors that are taken into account bythe researcher.
12. Prognostic life expectancy of the patient with effective antibiotictherapy and proper maintenance treatment is estimated by the researcher tobe at least 6 months.
13. Women who capable of childbirth (i.e. not in menopause and not surgicallysterilized) should have a negative pregnancy test result beforerandomization. Participants in the study who are capable of procreation,or sexual partners of participants who are capable of childbirth, shouldagree to the continued use of a highly effective method of contraceptionfrom the beginning of screening to the end of the study (medical andpedagogical observations) (highly effective methods of contraceptioninclude hormonal implants, plasters, injectable hormones, oral hormonalcontraceptives, intrauterine systems, approved cervical ring, priorbilateral ovariectomy, prior hysterectomy, previous bilateral tuballigation, true abstinence from sexual activity (if confirmed by theresearcher), or vasectomy with a partner.
14. Male participants of the study will need to use condoms with spermicideduring sexual intercourse during screening up to the end of the study incase of possible and even existing pregnancy of the sexual partner.

Exclusion Criteria:

1. Presence of any known or suspected disease, or condition that may distort theassessment effectiveness, including, but not limited to, the following:

• perinephral abscess;

• corticomedullary kidney abscess;

• any history of pelvic or urinary tract injury within 30 days prior to thestudy;

• polycystic kidney disease;

• chronic vesicoureteral reflux;

• prior or planned kidney transplantation;

• dialysis patients, including those under hemodialysis, peritoneal dialysis orcontinuous venovenous hemofiltration (CVVH);

• previous or planned cystectomy or surgery on the loop of ileum;

• presence of a known or suspected infection that is caused by fungi (e.g.candiduria) or mycobacteria (e.g. urogenital tuberculosis).

2. Presence of suspected or confirmed acute bacterial prostatitis, orchitis,epididymitis or chronic bacterial prostatitis determined by anamnesisand/or general medical examination.
3. Macrogematuria requiring treatment other than administration of the drugunder study or removal, or replacement of the urinary catheter.
4. Surgery on the urinary tract within 7 days before randomization, orsurgery on the urinary tract planned during the period of study (exceptsurgical intervention necessary to remove the obstruction or placement ofthe stent or holding of a nephrostomy until the end of treatment (medicaland pedagogical observations).
5. Renal function in screening evaluated by creatinine clearance as < 50 ml /min using the Cocroft-Gault formula and serum creatinine values obtainedin a local laboratory.
6. Source of infection diagnosed within 7 days prior to randomization withknown extra-renal origin, such as endocarditis, osteomyelitis, abscess,burn urinary tract infection; meningitis or pneumonia.
7. Any signs of sepsis, including shock or deep arterial hypotension, whichis defined as SBP < 90 mm Hg or a pressure reduction of > 40 mm Hg fromthe initial level (if known) not reacting to the load with a liquid.
8. Pregnant or breastfeeding women. 9. Established epileptic syndromerequiring ongoing treatment with an anticonvulsant drug, which will notallow the patient to comply with the treatment regimen according to theStudy Protocol. Patients with a history of epilepsy or those receivingstable therapy (i.e. unchanged therapy for 30 days) with a well-controlledepileptic syndrome (i.e. with no recurrence within the last 30 days) maybe considered for admission to the study.
9. Treatment with antitumor chemotherapeutic drugs, treatment withimmunosuppressive therapy for transplantation, or drugs preventingrejection of the transplant within 30 days prior to randomization.
10. Signs of severe disease or liver dysfunction, including confirmed viralhepatitis or hepatic encephalopathy.
11. AST or ALT > 3 x ULN (upper limit of normal) or total bilirubin > 1.5 xULN at screening.
12. Administration of any long-acting systemic antibiotic (i.e. with afrequency of less than once per day) for less than 12 hours prior torandomization.

However, the following patients may be included:

• who have received antimicrobial therapy for > 24 hours and have not responded to treatment (i.e. signs and symptoms have worsened) and have documented complicated UTIs caused by pathogen microorganisms resistant to previous therapy;

• who developed signs and symptoms of complicated UTI in the administration ofsystemic antibiotics for other indications, including antimicrobial prophylaxisagainst recurrent UTI;

• who received short-acting systemic antibiotic therapy (i.e. with frequency ofadministration more than once per day) for 24 hours before randomization, but notless than 12 hours prior to randomization.

14. Need for additional systemic antimicrobial therapy at the time of randomization (including antibiotic, antifungal therapy), other than treatment with the drugunder study, except for a single oral administration of any antifungal drug forthe treatment of vaginal candidiasis.

15. Likelihood of the need for an antibiotic to prevent complicated UTI duringpatient participation in the study (from randomization to medical andpedagogical observations).

16. Impossibility of removal or replacement of temporary catheters installed inmore than 24 hours prior to the screening from the perspective of evaluatingthe safety of the patient or presence of contraindications to manipulation (temporary catheters installed more than 24 hours prior to the screening shouldbe removed or replaced prior to collecting the urine sample for analysis andsowing).

17. History of HIV infection. 18. Presence of significant immunodeficiency orimmune deficiency, including hematologic malignant disease, bone marrowtransplantation or receiving immunosuppressive therapy, such as chemotherapyfor cancer, administration of drugs to prevent graft rejection and long-termuse of systemic corticosteroids (equivalent to the use of prednisone orequivalent systemic drug at a dose ≥ 20 mg/day for ≥ 2 weeks).

18. Presence of neutropenia (absolute number of neutrophils < 1000/mm3) based onthe results of the screening analysis in the central laboratory.

19. Presence of thrombocytopenia (especially in patients diagnosed withdisseminated intravascular coagulation or risk of serious bleeding) 50,000platelets/mm3 confirmed on the basis of indicators obtained in the centrallaboratory during screening.

20. Lactose intolerance, lactose deficiency or glucose-galactose absorption, severehypersensitivity or allergic reaction to β-lactam antibiotics, L-arginine,local anesthetics, antiarrhythmics or to the components of the drug inanamnesis.

21. Presence of any contraindications to the use of β-lactam antibiotics (cephalosporins, penicillins, carbapenems or monobactams), to administration ofauxiliary substances that are part of the relevant dosage forms.

22. Participation in another clinical trial using the drug or device under studyfor the last 90 days prior to randomization.

23. Inability or unwillingness to comply with the requirements of the StudyProtocol.

24. Any patients previously randomized into this study.