Evaluate Safety, Tolerability, and Pharmacokinetics of Single and Repeat IV Doses

GSK2140944 belongs to the Bacterial Type II Topoisomerase Inhibitor (BTI) class of antibiotics. GSK2140944 has demonstrated in vitro and in vivo activity against Gram positive pathogens including methicillin resistant Staphylococcus aureus (MRSA) and Gram-negative pathogens associated with respiratory tract, skin and soft tissue infections including isolates resistant to existing classes of antimicrobials.

GSK2140944 belongs to the Bacterial Type II Topoisomerase Inhibitor (BTI) class of antibiotics. GSK2140944 has demonstrated in vitro and in vivo activity against Gram positive pathogens including methicillin resistant Staphylococcus aureus (MRSA) and Gram-negative pathogens associated with respiratory tract, skin and soft issue infections including isolates resistant to existing classes of antimicrobials. This study will be the first administration of GSK2140944 as an intravenous (IV) formulation in humans and will be conducted in two (2) parts. Single IV doses will be explored in Part A and repeat IV doses will be explored in Part B. In addition, this study will evaluate the absolute bioavailability of an oral capsule formulation as compared to the IV formulation in Part A. Both study parts will investigate the safety, tolerability and pharmacokinetic profile of GSK2140944 in healthy adult subjects.

Eligibility Criteria:
Inclusion Criteria:

* AST, ALT, alkaline phosphatase and bilirubin less than and equal to 1.5xULN (isolated bilirubin less than 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35%).
* Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* Male or female between 18 and 60 years of age inclusive, at the time of signing the informed consent.
* A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. To confirm post-menopausal status, a blood sample for simultaneous follicle stimulating hormone (FSH) greater than 40 MlU/ml and estradiol less than 40 pg/ml (less than 147 pmol/L) is confirmatory. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until the final follow-up visit.
* Body weight greater than and equal to 50 kg and BMI within the range 19 - 31 kg/m2 (inclusive).
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Exclusion Criteria:

* A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening or positive Human Immunodeficiency Virus (HIV) antibody.
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
* Any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal conditions or history of such conditions that, in the opinion of the investigator may place the subject at an unacceptable risk as a participant in this trial or may interfere with the absorption, distribution, metabolism or excretion of drugs.
* A positive urine test for drugs of abuse or alcohol (or alcohol breath test) at screening.
* A screening urinalysis positive for protein or glucose (greater than "trace" findings of protein or glucose).
* A serum creatinine value between screening and Day -1 visit that is increased by more than 0.2 mg/dL (or 15.25 umol/L) changes.
* History of photosensitivity to quinolones.
* Unwillingness to commit to avoid excessive exposure to sunlight (or exposure whilst on a tanning bed) which would cause a sunburn reaction from first dose up to and including the follow-up visit.
* History of drug abuse within 6 months of the study.
* History of smoking or use of nicotine containing products within 3 months of screening, or a positive urine cotinine indicative of smoking at screening.
* History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of greater than 21 units (or an average daily intake of greater than 3 units) for males or an average weekly intake of greater than 14 units (or an average daily intake greater than 2 units) for females. One unit is equivalent to 270 mL of full strength beer, 470 mL of light beer, 30 mL of spirits and 100 mL of wine.
* The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication.
* Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, or use of St. John's Wort within 14 days prior to the first dose of study medication. By exception, the volunteer may take paracetamol or acetaminophen (less than and equal to 2 grams/day) up to 48 hours prior to the first dose of study medication. However, the Investigator and GSK study team can review medication on a case by case basis to determine if its use would compromise subject safety or interfere with the study procedures or data interpretation.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
* Donation of blood in excess of 500 mL within 12 weeks prior to dosing.
* Unwillingness or inability to follow the procedures outlined in the protocol.
* History of tendon rupture.
* Subject is mentally or legally incapacitated.
* History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula patency).
* Consumption of red wine, seville oranges, grapefruit or grapefruit juice, pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices containing such products from 7 days prior to the first dose of study medication.
* Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): Heart rate: Males - less than 40 and greater than 100 bpm; Females: less than 50 and greater than 100 bpm; PR Interval: Males and Females - less than 120 and greater than 220 msec; QRS duration: Males and Females - less than 70 and greater than 100 msec; QTcB or QTcF interval: Males and Females - greater than 450 msec; Evidence of previous myocardial infarction (does not include ST segment changes associated with repolarization); Subject has Bundle Branch Block; Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block \[2nd degree or higher\], Wolf Parkinson White \[WPW\] syndrome), sinus pauses greater than 3 seconds, non-sustained or sustained ventricular tachycardia (greater than and equal to 3 consecutive ventricular ectopic beats) or any significant arrhythmia which, in the opinion of the principal investigator and GSK medical monitor, will interfere with the safety of the individual subject.
* Screening holter monitoring shows one or more of the following: Any symptomatic arrhythmia (except isolated extra systoles); Sustained cardiac arrhythmias (such as atrial fibrillation or flutter, SVT (greater than 10 consecutive beats)); Sinus tachycardia (or supraventricular tachycardia) greater than 150 bpm; Non-sustained or sustained ventricular tachycardia (defined as greater than and equal to 3 consecutive ventricular ectopic beats); Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block \[2nd degree or higher in an awake subject\], WPW syndrome, other pre-excitation syndromes); Symptomatic sinus pause or sinus pause \>3 seconds - unless patient is straining, vomiting, or having some other type of hypervagal response; 300 or more supraventricular ectopic beats in 24 hours; 250 or more ventricular ectopic beats in 24 hours; Ischemia, diagnosed by a sequence of EKG changes that include flat or downsloping ST-segment depression greater than 0.1 mV, with a gradual onset and offset that lasts for a minimum period of 1 minute. Each episode of ischemia must be separated by a minimum duration of at least 1 minute, during which the ST segment returns back to baseline (1x1x1 rule).
* Neutrophil count \<2000 cells per microliter (a single repeat is allowed for eligibility determination).