GSK2251052 in Complicated Urinary Tract Infection
GSK2251052 in Complicated Urinary Tract Infection
This study is being conducted to evaluate the safety, efficacy (clinical and
 microbiological), pharmacokinetics/pharmacodynamics of GSK2251052 and to assess whether it
 would be a suitable antibiotic for the treatment for febrile lower cUTI and
 pyelonephritis(complicated and uncomplicated). GSK2251052 will be compared to
 imipenem-cilastatin, which is an antibiotic commonly used to treat serious cUTI infections.
 GSK2251052 has a spectrum of microbiological activity that includes pathogens responsible for
 cUTI.
Inclusion Criteria:

 - Adult subjects least 18 years of age.

 N.B. Females of non-childbearing or childbearing potential may be enrolled. Females of
 childbearing potential must have a negative pregnancy test at study entry and must have
 practiced adequate contraception for at least 30 days prior to study entry. Additionally,
 the subject agrees to one of the following methods for avoidance of pregnancy during the
 entire study treatment period:

 -  Abstinence; or,

 -  Oral Contraceptive, either combined estrogen/progesterone or progesterone alone, PLUS
 an additional barrier method [ie, condom, occlusive cap (diaphragm or cervical/vault
 caps) or vaginal spermicidal agent (foam/gel/film/cream/suppository)]; or,

 -  Injectable progesterone; or

 -  Implants of levonorgestrel; or,

 -  Estrogenic vaginal ring; or,

 -  Percutaneous contraceptive patches; or

 -  Intrauterine device (IUD) or intrauterine system (IUS) showing that failure rate is
 less than 1% in the IUD or IUS product label; or,

 -  Has a male partner who is sterilized (vasectomy with documentation of azoospermia).

 -  Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps)
 with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

 -  Females are considered to be of non-childbearing potential if they have documented
 tubal ligation or hysterectomy; or are postmenopausal, defined as 12 months of
 spontaneous amenorrhea [in questionable cases a blood sample with simultaneous
 follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L)
 is confirmatory]

 -  Subject requires hospitalisation and has clinical signs and symptoms of lower cUTI or
 pyelonephritis (complicated or uncomplicated) as defined below, that requires
 parenteral treatment only with a treatment course of a minimum of 5 days and a maximum
 of 14 days:

 -  Lower cUTI - subjects must have documented fever defined as >38°C oral, >38.5°C
 tympanic or >39°C rectal, within the last 24 hours exceptions would be:

 -  Afebrile subjects with lower cUTI who have a white blood cell count (WBC) ≥15,000
 cells/mm3

 -  Afebrile subjects with a lower cUTI following requiring parenteral therapy due to a
 specific indication e.g. before and during an operative procedure, when oral
 antibiotics are not indicated or in cases where the cUTI is suspected to be due to a
 pathogen resistant to current oral antibiotics

 -  and at least two of the following UTI symptoms including dysuria, frequency, urgency
 or suprapubic pain, with the presence of a complicating factor:

 -  Male gender;

 -  Current bladder instrumentation or indwelling urinary catheter that has to be removed
 two days before the end of IV study drug administration;

 -  Obstructive uropathy that is expected to be medically or surgically treated during the
 course of IV study drug administration;

 -  Urogenital surgery within 7 days preceding administration of the first dose of study
 drug;

 -  Functional or anatomical abnormality of the urogenital tract including anatomic
 malformations or neurogenic bladder with voiding disturbance of at least 100 mL
 residual urine.

 -  Acute pyelonephritis (complicated or uncomplicated): subjects must have documented
 fever defined as >38°C oral, >38.5°C tympanic or >39°C rectal, within the last 24
 hours and flank pain or costovertebral angle tenderness (CVA). Complicating factors
 for pyelonephritis are the same as for complicated UTI.

 -  Subject has pyuria (white blood cell [WBC] count > 10/µL (or >5/high-power field [HPF]
 in a conventional urinalysis) in unspun clean-catch midstream urine (MSU) or catheter
 urine sample or >= 10 WBC/HPF in spun MSU or catheter urine).

 -  Subject has Gram-negative organism(s) on direct examination of a Gram-stained specimen
 from unspun or spun MSU or catheter urine sample.

 -  Subject has provided a pre-therapy urine specimen obtained within 48 hours prior to
 the start of therapy, which when cultured has grown at least one and not more than two
 Gram-negative uropathogens at >=10^5 CFU/mL.

 -  A subject may be enrolled before the results of the pre-therapy urine culture is
 known, but the subject should be withdrawn from the study if the culture does not
 yield at least one but not more than two qualifying Gram-negative uropathogens at
 >=10^5 CFU/mL or if the culture yields Gram-positive uropathogens.

 -  A subject with lower cUTI or pyelonephritis (complicated or uncomplicated) who has
 failed a previous antibacterial treatment regimen is eligible provided a urine
 specimen is positive for one and not more than two bacterial Gram-negative
 uropathogens at >=10^5 CFU/mL. Subjects who are treatment failures due to
 imipenem-cilastatin should not be enrolled.

 -  QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block

 -  Exclusion Criteria:

 Subjects meeting any of the following criteria must not be enrolled in the study:

 -  Concomitant infection requiring systemic antibacterial therapy other than study drugs
 at the time of randomisation.

 -  Subject is known to have one or more of the following:

 -  A urinary catheter that is not being removed during the study (or with an expectation
 that a catheter would be inserted during therapy with study drug and subsequently not
 removed during the study period; (intermittent straight catheterisation is acceptable)

 -  Complete permanent obstruction of the urinary tract;

 -  A permanent indwelling catheter or comparable instrumentation including nephrostomy
 that will not be removed during IV study drug administration

 -  Suspected or confirmed prostatitis

 -  Suspected or confirmed perinephric or intrarenal abscess

 -  A UTI suspected or confirmed to be fungal in origin (with >= 10^3 fungal CFU/mL)

 -  A UTI suspected or confirmed to be due to a Gram-positive uropathogen(s), with >= 10^5
 Gram-positive organism CFU/mL;

 -  A UTI known at study entry to be caused by a pathogen(s) resistant to the study
 antimicrobial agent;

 -  Known ileal loops or vesico-ureteral reflux ;

 -  Polycystic kidney disease.

 -  Subject has an APACHE II score >20

 -  Subject has known severe impairment of renal function including: a calculated
 creatinine clearance (CrCl) of less than 50 mL/min; requirement for peritoneal
 dialysis, haemodialysis, or haemofiltration; oliguria (less than 20 mL urine output
 per hour over 24 hours);

 -  Subject with an intractable lower cUTI requiring more than 14 Days IV treatment.

 -  Subjects with asymptomatic lower cUTI, such as subjects with spinal cord injury with
 lower cUTI who are not able to perceive symptoms due to their injury.

 -  Subject with lower cUTI or pyelonephritis (complicated and uncomplicated) who has
 received any amount of a potentially therapeutic antibiotic within the 96 h before
 providing the baseline urine culture specimen or prior to the start of the study.

 -  Subject has Gram-positive organism(s) on direct examination of a Gram-stained specimen
 of spun/unspun MSU or catheter urine.

 -  Subject is considered unlikely to survive the 4 6 week study period or has any rapidly
 progressing disease or immediately life-threatening illness (including acute hepatic
 failure, respiratory failure or septic shock).

 -  Subject has evidence of known or pre-existing severe hepatic disease (Child-Pugh score
 of B or C).

 -  Subject has a known baseline haemoglobin less than 10 g/dL ,haematocrit less than 30%
 and/or a known reticulocyte count of >5% (i.e., reticulocytes >5% of total RBC mass)

 -  Subject has known neutropenia or is anticipated to develop neutropenia during the
 course of the study (i.e., new chemotherapy subject), with absolute neutrophil count
 less than 1000 cells/mm3

 -  Subject has a known platelet count less than 75,000 cells /mm3 (subjects with platelet
 counts as low as 50,000 cells /mm3 are eligible if the reduction is historically
 stable).

 -  Subject has an immunocompromising illness; including known human immunodeficiency
 virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), organ (including
 bone marrow) transplantation, hematological malignancy, and/or immunosuppressive
 therapy , including high-dose corticosteroids (e.g., greater than 40 mg prednisone or
 equivalent per day for greater than two weeks)

 -  Subject has participated in any investigational drug or device study within 30 days of
 study entry or within 5 half-lives, whichever is longer.

 -  Subject has previously received treatment with GSK2251052.

 -  Subject has a prior history of seizures or has a CNS abnormality predisposing them to
 seizures or has a lowered seizure threshold and/or is using concomitant medications
 with seizure potential.

 -  Subject requires probenicid or valproic acid medications.

 -  Subject has a history of moderate or severe hypersensitivity to beta-lactam
 antibiotics.

 -  Subject is pregnant or nursing

 -  Subject, in the opinion of the investigator may be significantly compromised by a
 potential drop in haemoglobin ≥2.5g/dl which is not related to the condition under
 study

 -  French subjects: the French subject has participated in any study using an
 investigational drug during the previous 30 days