• Number of subjects with clinical response at the TOC visit [ Time Frame: Up to Day 13 ]
  The clinical signs and symptoms score for acute cystitis will be used to programmatically determine the clinical outcome and response.
• Number of subjects with indicated clinical outcome at the TOC visit [ Time Frame: Up to Day 13 ]
  The clinical signs and symptoms score for acute cystitis will be used to programmatically determine the clinical outcome and response.
• Number of subjects with clinical response at the follow-up visits [ Time Frame: Up to Day 31 ]
  The clinical signs and symptoms score for acute cystitis will be used to programmatically determine the clinical outcome and response.
• Number of subjects with indicated clinical outcome at the follow-up visits [ Time Frame: Up to Day 31 ]
  The clinical signs and symptoms score for acute cystitis will be used to programmatically determine the clinical outcome and response.
• Number of subjects with microbiological response at the TOC visit [ Time Frame: Up to Day 13 ]
  The microbiological response to study treatment will be determined by pre-specified programmed algorithm for each subject or uropathogen.
• Number of subjects with indicated microbiological outcome at the TOC visit [ Time Frame: Up to Day 13 ]
  The microbiological outcome to study treatment will be determined by pre-specified programmed algorithm for each subject or uropathogen. The microbiological outcome by baseline qualifying uropathogen will be determined by comparing the baseline culture results to the culture results at each subsequent visit.
• Number of subjects with microbiological response at the follow-up visits [ Time Frame: Up to Day 31 ]
  The microbiological response to study treatment will be determined by pre-specified programmed algorithm for each subject or uropathogen.
• Number of subjects with indicated microbiological outcome at the follow-up visits [ Time Frame: Up to Day 31 ]
  The microbiological outcome to study treatment will be determined by pre-specified programmed algorithm for each subject or uropathogen. The microbiological outcome by baseline qualifying uropathogen will be determined by comparing the baseline culture results to the culture results at each subsequent visit.
• Number of subjects with therapeutic response at follow-up visits [ Time Frame: Up to Day 31 ]
  A therapeutic success refers to subjects who have been deemed both a "microbiological success" and a "clinical success". All other combinations (other than clinical success + microbiological success) will be deemed failures for therapeutic response.
• Peak concentration of gepotidacin in plasma [ Time Frame: Day 1 ]
  Blood samples will be collected for analysis of peak concentration of gepotidacin in plasma.
• Trough concentration of gepotidacin in plasma [ Time Frame: Up to Day 3 ]
  Blood samples will be collected for analysis of trough concentration of gepotidacin in plasma.
• Peak concentration of gepotidacin in urine [ Time Frame: Day 1 ]
  Urine samples will be collected for analysis of peak concentration of gepotidacin in urine.
• Trough concentration of gepotidacin in urine [ Time Frame: Up to Day 3 ]
  Urine samples will be collected for analysis of trough concentration of gepotidacin in urine.
• Number of subjects with Treatment-emergent adverse events and serious adverse events (SAEs) [ Time Frame: Up to Day 31 ]
  An adverse event (AE) is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose; results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, any other situation that require medical or scientific judgment.
• Change from Baseline in neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count and platelet count [ Time Frame: Baseline and up to Day 13 ]
  Blood samples will be collected for the assessment of neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count and platelet count. All parameters have "Giga cells per Liter" as unit of measure.
• Change from Baseline in hemoglobin level [ Time Frame: Baseline and up to Day 13 ]
  Blood samples will be collected for the assessment of hemoglobin level.
• Change from Baseline in hematocrit level [ Time Frame: Baseline and up to Day 13 ]
  Blood samples will be collected for the assessment of hematocrit level.
• Change from Baseline in red blood cell (RBC) count [ Time Frame: Baseline and up to Day 13 ]
  Blood samples will be collected for the assessment of RBC count.
• Change from Baseline in mean corpuscular hemoglobin (MCH) [ Time Frame: Baseline and up to Day 13 ]
  Blood samples will be collected for the assessment of MCH.
• Change from Baseline in mean corpuscular volume (MCV) [ Time Frame: Baseline and up to Day 13 ]
  Blood samples will be collected for the assessment of MCV.
• Change from Baseline in blood urea nitrogen, glucose non-fasting, calcium, chloride, sodium and potassium levels [ Time Frame: Baseline and up to Day 13 ]
  Blood samples will be collected for the assessment of blood urea nitrogen, glucose non-fasting, calcium, chloride, sodium and potassium levels. All parameters have "Millimole per Liter" as unit of measure.
• Change from Baseline in total bilirubin, direct bilirubin and creatinine levels [ Time Frame: Baseline and up to Day 13 ]
  Blood samples will be collected for the assessment of total bilirubin, direct bilirubin and creatinine levels. All parameters have "Micromoles per Liter" as unit of measure.
• Change from Baseline in albumin and total protein levels [ Time Frame: Baseline and up to Day 13 ]
  Blood samples will be collected for the assessment of albumin and total protein levels. All parameters have "Gram per Liter" as unit of measure.
• Change from Baseline in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase levels [ Time Frame: Baseline and up to Day 13 ]
  Blood samples will be collected for the assessment of AST, ALT and alkaline phosphatase levels. All parameters have "International units per Liter" as unit of measure.
• Number of subjects with abnormal urinalysis Dipstick results [ Time Frame: Up to Day 13 ]
  Urine samples will be collected to assess pH, glucose, protein, blood and ketones by Dipstick method.
• Change from Baseline in specific gravity of urine [ Time Frame: Baseline and up to Day 13 ]
  Urine samples will be collected for the measurement of specific gravity.
• Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) [ Time Frame: Baseline and up to Day 13 ]
  SBP and DBP will be assessed in the semi-supine position after 5 minutes rest.
• Change from Baseline in pulse rate [ Time Frame: Baseline and up to Day 13 ]
  Pulse measurements will be assessed in the semi-supine position after 5 minutes rest.
• Change from Baseline in body temperature [ Time Frame: Baseline and up to Day 13 ]
  Changes in body temperature from Baseline will be assessed.

• Drug: Gepotidacin
  Gepotidacin will be available as tablets containing 750 mg gepotidacin. Each dose should be taken with water after consumption of food.
• Drug: Placebo matching nitrofurantoin
  Placebo matching nitrofurantoin will be available as over-encapsulated unit-dose capsules. Each dose should be taken with water after consumption of food.
• Drug: Nitrofurantoin
  Nitrofurantoin will be available as over-encapsulated capsules containing 25 mg nitrofurantoin macrocrystals and 75 mg nitrofurantoin. Each dose should be taken with water after consumption of food.
• Drug: Placebo matching gepotidacin
  Placebo matching gepotidacin will be available as unit-dose gepotidacin placebo-to-match tablet. Each dose should be taken with water after consumption of food.

• Active Comparator: Gepotidacin
  Subjects will be administered oral doses of 1500 mg gepotidacin plus nitrofurantoin matching placebo twice daily (BID); approximately every 12 hours for 5 days
  Interventions:

  • Drug: Gepotidacin
  • Drug: Placebo matching nitrofurantoin
• Active Comparator: Nitrofurantoin
  Subjects will be administered oral doses of 100 mg nitrofurantoin plus gepotidacin matching placebo BID; approximately every 12 hours for 5 days.
  Interventions:

  • Drug: Nitrofurantoin
  • Drug: Placebo matching gepotidacin

Inclusion Criteria:

• Subjects having >=12 years of age at the time of signing the informed consent.
• Subjects having body weight of >45 kilogram (kg).
• Subjects having 2 or more of the following clinical signs and symptoms of acute cystitis with onset <=72 hours prior to study entry: dysuria, frequency, urgency, or lower abdominal pain.
• Subjects having nitrite or pyuria (>15 white blood cells [WBC]/ high power field [HPF] or the presence of 3+/moderate leukocyte esterase) from a pretreatment clean-catch midstream urine sample based on local laboratory procedures.
• Female subjects are included.
• Female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a woman of childbearing potential (WOCBP) or A WOCBP who agrees to follow the contraceptive guidance (to abstain from sexual activity to prevent possible re-infection) from the Baseline Visit through completion of the TOC Visit.
• Subject is capable of giving signed informed consent/assent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF)/assent form and in this protocol.

Exclusion Criteria:

• Subjects reside in a nursing home or dependent care type-facility.
• Subject has a body mass index >=40.0 kilogram per square meter (kg/m^2) or a body mass index >=35.0 kg/m^2 and is experiencing obesity-related health conditions such as high blood pressure or uncontrolled diabetes.
• Subject has a history of sensitivity to the study treatments, or components thereof, or a history of a drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates her participation.
• Subject is immunocompromised or has altered immune defenses that may predispose the subject to a higher risk of treatment failure and/or complications. For example, uncontrolled diabetes, renal transplant recipients, subjects with clinically significant persistent granulocytopenia (absolute neutrophil count <1000 per microliter [μL]), and subjects receiving immunosuppressive therapy, including corticosteroid therapy [>40 mg per day prednisolone or equivalent for >1 week, >=20 mg per day prednisolone or equivalent for >2 weeks, or prednisolone or equivalent >=10 mg per day for >6 weeks]). Subjects with a known cluster of differentiation 4 (CD4) count of <200 cells per cubic millimeter (cells/mm^3) should not be enrolled.
• Subject has a medical condition that requires medication that may be impacted by inhibition of acetylcholinesterase, such as, Poorly controlled asthma or chronic obstructive pulmonary disease at Baseline and, in the opinion of the investigator, not stable on current therapy or acute severe pain, uncontrolled with conventional medical management or active peptic ulcer disease or parkinson disease or myasthenia gravis or a history of seizure disorder requiring medications for control (this does not include a history of childhood febrile seizures) or subject has any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study treatment (For example, ileostomy or malabsorption syndrome).
• Subject has a known glucose-6-phosphate dehydrogenase deficiency.
• Subject, in the judgment of the investigator, would not be able or willing to comply with the protocol or complete study follow-up.
• Subject has a serious underlying disease that could be imminently life-threatening, or the subject is unlikely to survive for the duration of the study period.
• Subject has acute cystitis that is known or suspected to be due to fungal, parasitic, or viral pathogens; or known or suspected to be due to Pseudomonas aeruginosa or Enterobacteriaceae (other than E. coli) as the contributing pathogen.
• Subject has symptoms known or suspected to be caused by another disease process, such as asymptomatic bacteriuria, overactive bladder, chronic incontinence, or chronic interstitial cystitis, that may interfere with the clinical efficacy assessments.
• Subject has an anatomical or physiological anomaly that predisposes the subject to UTIs or may be a source of persistent bacterial colonization, including calculi, obstruction or stricture of the urinary tract, primary renal disease (for example, polycystic renal disease), or neurogenic bladder, or the subject has a history of anatomical or functional abnormalities of the urinary tract (for example, chronic vesico-ureteral reflux, detrusor insufficiency).
• Subject has an indwelling catheter, nephrostomy, ureter stent, or other foreign material in the urinary tract.
• Subject who, in the opinion of the investigator, has an otherwise complicated UTI, an active upper UTI (for example, pyelonephritis, urosepsis), signs and symptom onset >=96 hours before study entry, or a temperature >=101 Degrees Fahrenheit (F), flank pain, chills, or any other manifestations suggestive of upper UTI.
• Subject has known anuria, oliguria, or significant impairment of renal function (creatinine clearance <60 mL/min or clinically significant elevated serum creatinine as determined by the investigator).
• Subject presents with vaginal discharge at Baseline, for example, suspected sexually transmitted disease.
• Subject has congenital long QT syndrome or known prolongation of the corrected QT (QTc) interval.
• Subject has uncompensated heart failure.
• Subject has severe left ventricular hypertrophy.
• Subject has a family history of QT prolongation or sudden death.
• Subject has a recent history of vasovagal syncope or episodes of symptomatic bradycardia or brady-arrhythmia within the last 12 months.
• Subject is taking QT-prolonging drugs or drugs known to increase the risk of torsades de pointes (TdP) per the www.crediblemeds.org. "Known Risk of TdP" category at the time of her Baseline Visit, which cannot be safely discontinued from the Baseline Visit to the TOC Visit; or the subject is taking a strong cytochrome P450 enzyme 3A4 (CYP3A4) inhibitor or a strong P-glycoprotein (P-gp) inhibitor.
• For any subject >=12 to <18 years of age, the subject has an abnormal electrocardiogram (ECG) reading.
• Subject has a QTc >450 millisecond (msec) or a QTc >480 msec for subjects with bundle-branch block.
• Subject has a documented or recent history of uncorrected hypokalemia within the past 3 months.
• Subject has a known alanine aminotransferase (ALT) value >2 times upper limit of normal (ULN).
• Subject has a known bilirubin value >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Subject has a current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), including symptomatic viral hepatitis or moderate-to-severe liver insufficiency (Child Pugh class B or C).
• Subject has a previous history of cholestatic jaundice or hepatic dysfunction associated with nitrofurantoin.
• Subject has received treatment with other systemic antimicrobials or systemic antifungals within 1 week before study entry.
• Subject must agree not to use the medications or nondrug therapies from the Baseline Visit through the TOC Visit.
• Subject has been previously enrolled in this study or has previously been treated with gepotidacin.
• Subject has participated in a clinical trial and has received an investigational product within 30 days or 5 half-lives, whichever is longer.