Japanese guideline for clinical research of antimicrobial agents on urogenital infections: Second edition.

Abstract

To determine criteria for objective evaluation of the efficacy of antimicrobial agents for urogenital infections in Japan, researchers involved in urinary tract infections (UTIs) gathered to establish the first criteria, “Criteria for the clinical evaluation of drug efficacy in UTI”, in the 1970s, and then the criteria were revised until the third edition was reported. Meanwhile, guidelines such as those of the IDSA and FDA in the United States or the European guidelines providing the criteria for clinical evaluation of drug efficacy, etc., were established, and international harmonization along with globalization of the development of antimicrobial agents became necessary. To meet this trend and use the data accumulated in Japan interchangeably with these criteria, the committee on clinical evaluation for antimicrobial agents against UTI in Japanese Society of Chemotherapy discussed the criteria and established the “Criteria for the clinical evaluation of drug efficacy in UTI, 4th edition, interim proposal and supplement” in 1996. Thereafter, international joint development, extrapolation of foreign data, and the introduction of bridging studies have taken place, and the need for further international harmonization has increased. However, because there were many differences between Western countries and Japan in the pathogenesis or diagnosis of UTIs and the concept of the assessments of clinical evaluations and clinical cures, many points relating to international harmonization had to be discussed. Therefore, a committee to review criteria for the clinical evaluation of drug efficacy in UTI of the Japanese Society of Chemotherapy was established again, and the above criteria, for the clinical evaluation of drug efficacy in UTI were extensively revised in November 2009 and were organized with the name changed to “Guidelines for the implementation of clinical trials for urogenital infections, 1st edition”. Recently, because the FDA guidance in US for clinical trials of complicated UTI was reviewed and inconsistencies were present in the entry criteria such as bacterial counts in urine between the guidance and the 1st edition, which is mentioned above, a committee was established in the Japanese Society of Chemotherapy to revise the guidelines for the implementation of clinical trials for urogenital infections, and a complete revision of the 1st edition was discussed. The revised edition was completed through that process and has been published under the title “Japanese guideline for clinical research of antimicrobial agents on urogenital infections: second edition”. This guideline aims to objectively evaluate the efficacy of antimicrobial agents for the treatment of urinary tract infections (UTIs). The criteria presented in this guideline aim to absolutely ensure urogenital infections for clinical trials. Therefore, it should be noted that the criteria listed in this guideline are not for the diagnosis of or assessment of therapeutic effect on urogenital infections. We have made efforts to allow use of the guideline in both general clinical studies and comparative studies and objective comparisons of individual study results. We have established the minimum necessary criteria in the guideline so that there is allowance to change items when considering individual cases or according to the practice of each institution. Urological infections are classified as UTIs (cystitis, pyelonephritis) and genital infections (urethritis, prostatitis, epididymitis) according to the site of infection. These infections are non-specific inflammations caused by common bacteria and are not specific inflammations caused by fungi, Mycobacterium species, viruses, etc. UTIs include acute uncomplicated cystitis, acute uncomplicated pyelonephritis, and complicated UTI. UTIs are classified as acute or chronic according to the clinical course, as uncomplicated and complicated by the underlying disease, and as cystitis and pyelonephritis by the site of infection. Generally, the disease name is based on a combination of the clinical course, underlying disease, and site of infection. Although uncomplicated UTIs are infections with no underlying disease that could affect urination, complicated UTIs of a limited sense are defined as infections with underlying disease that could affect urination, and complicated UTIs of wider sense are infections with underlying disease (diabetes, immunosuppression, etc.) that could induce, exacerbate, and prolong the UTI, in addition to infections in the limited sense and infections in men. Complicated UTIs were defined in the conventional Criteria for Evaluation of Clinical Efficacy of Antimicrobial Agents on UTI as infections with underlying disease in the urinary tract; namely, complicated UTIs in the limited sense. Considering the following facts, that: (1) complications such as diabetes can induce, exacerbate, and prolong UTIs, as can underlying diseases in the urinary tract; (2) UTIs are retrograde infections, such that men tend not to develop retrograde infection compared with women, in whom the urethra is 10 times shorter than that in men; and (3) even if a male patient is diagnosed as having no underlying diseases in the urinary tract, further examination finds that most male patients with UTI have underlying diseases, including impaired urine excretion, we have decided to use the definition of complicated UTIs in the wider sense in this guideline. It is preferable to exclude from the guideline patients with urinary diversion using intestinal segments or those with a catheter, other than a permanent catheter, because it is difficult to determine the response of such patients to antimicrobial agents. Genital infections include urethritis, acute bacterial prostatitis, and acute epididymitis. Prostatitis is classified into four categories according to clinical condition by the NIH: category I, acute bacterial prostatitis; category II, chronic bacterial prostatitis; category III, chronic pelvic pain syndrome/chronic pain syndrome associated with prostatitis (A, inflammatory; B, noninflammatory); and category IV, asymptomatic prostatitis. We include only category I; namely, acute bacterial prostatitis, in this guideline because the disease is clearly associated with bacteria, antimicrobial agents are used for the treatment of the disease, and it is possible to evaluate the efficacy of antimicrobial drugs over a relatively short period. In general, however, such an antimicrobial agent that is effective in acute bacterial prostatitis is also effective in chronic bacterial prostatitis. Likewise, regarding epididymitis, we include only acute epididymitis in the guideline. Age/sex: Individual diseases are determined. When a minor is included in the study, a thorough explanation of the details of the study is given to both the participant and the participant's parents or guardians at the time of agreement to enter the study. Clinical symptoms: This guideline evaluates the efficacy of antimicrobial agents against urogenital infections. It is preferable to exclude cases of colonization resulting from pathogenic microorganisms. Therefore, clinical symptoms caused by urogenital infections are defined, and it essential for the entry criteria that participants present these symptoms. Pyuria: Individual diseases are determined. However, the following test methods may also be used. In addition, when new methods equal to, or better than, these methods are developed, these methods will likely be replaced.–Microscopy of urinary sediment (For observation of pyuria alone, 500 g × 5 min is good, but for observation of bacteria, 500 g × 5 min is not sufficient, and it is preferable to extend the centrifugation time).–Urinary test strip (the principal measurement is esterase activity).–Counting chamber method that uses non-centrifuged urine (Kova Slide 10 GridⓇ, HYCOR Biomedical Inc., Garden Grove, CA).–Use of flow cytometry with non-centrifuged urine and a fully automatic urine analysis system is assumed to be fundamental (equal to or better than Sysmex UF-50Ⓡ, UF-100Ⓡ, UF110iⓇ, and UF-1000iⓇ [SYSMEX Corp., Kobe, Japan], and other systems). The number of bacteria is determined as an exclusion criterion. If the viable bacteria count before administration is <105 colony-forming units (CFU)/mL in a case, the bacteria are judged to be non-significant and the case is excluded. However, in cases of urethritis and chlamydial epididymitis, if Neisseria gonorrhoeae or Chlamydia trachomatis is not detected before administration, the cases are excluded. Of the bacteria isolated from urogenital tract, only the bacterial strains that have pathogenicity to urogenital tract are evaluated the efficacy of drug. However, when the bacterial levels beyond those already counted exceed the above-mentioned exclusion criteria, ‘‘acceptance’’ or ‘‘rejection’’ is decided after examining the details. In addition, when the pathogen type is clearly understood, it is possible to target that pathogen type. The standard duration of treatment is assumed to be from a single dose to 14 days, but this may differ according to the disease, and it is also determined according to the characteristics of the experimental drug. Basically, the final day a dose is given is considered to be the end of treatment with the experimental drug. However, when the half-life of a drug has effective blood and urine levels that continue for a longer period, the day on which it is estimated that no effective level of the drug is left in the bloodstream is considered to be the end of treatment with that drug. As a rule, the efficacy of the drug will be assessed 5–9 days after completion of therapy and 21–28 days after the start of therapy. The primary efficacy endpoint is made 5–9 days after completion of therapy. This is the period of time that would be needed for remaining bacteria to re-multiply after the antibiotic is ‘‘washed out’’ of the body. Special consideration must be given when a drug with a long half-life is used in high doses. However, in clinical trials of a parenteral drug, when the parenteral drug is switched to an oral drug after administration of the parenteral drug, the efficacy of treatment is assessed at the end of administration of the parenteral drug (about 4–6 days after the start of therapy) and assigned as one of the primary endpoint. Furthermore, in cases of infection by C. trachomatis and Mycoplasma genitalium, because it is difficult to culture these microorganisms, to avoid amplifying nucleic acid in dead bacteria and creating a false-positive reading, the nucleic acid amplification method should be performed 2–4 weeks after completion of therapy to evaluate bacteriological efficacy against nongonococcal urethritis.•Assessment of the efficacy of treatment on days 5–9 after the end of therapy and at the end of administration of a parenteral drug when the parenteral drug is switched to oral drug after administration of the parenteral drug in clinical trials of parenteral drugs:–Microbiological outcome: Based on the number of bacteria per bacterial strain of all urinary tract pathogens that were isolated before administration, an assessment is divided into 2 grades, “Eradication” or “Failure”: if an antimicrobial agent is effective on all bacterial strains, an assessment is judged to be “Eradication”, and if an antimicrobial agent is ineffective on any of the bacterial strains, an assessment is judged to be “Failure”. Moreover, if an assessment is judged to be “Failure”, it is divided into either “Resistant” or “Undeterminable”.–Clinical outcome: An assessment is divided into 2 grades, “Cure” or “Failure”, depending on the course of the symptoms, prolonged or transient. Symptoms that are present before the development of infection due to underlying diseases are not the subject of assessment.–Primary efficacy endpoint (primary endpoint): A case in which both the bacteriological effect and the clinical effect are favorable is judged as “Response”, and a case in which either the bacteriological effect or the clinical effect is unfavorable, or both are unfavorable, is judged as “Failure”.•Assessment of response 21–28 days after the start of therapy:–Microbiological outcome: Based on the number of bacteria per bacterial strain of the urinary tract pathogen, an assessment is divided into 2 grades: if an antimicrobial agent is effective against all bacterial strains, an assessment is judged to be “Eradication”, and if an antimicrobial agent is ineffective against any of the bacterial strains, an assessment is judged to be “Failure”.–Clinical outcome: Assessments are categorized as to ‘‘Cure’’ or ‘‘Failure’’ based on the presence or absence of symptoms.–Recurrence assessment: A case in which both the bacteriological effect and the clinical effect are favorable, is judged as “Response”, and a case in which either the bacteriological effect or the clinical effect is unfavorable, or both are unfavorable, is judged as “Failure”.•Clinical symptoms (Table 1)Table 1Clinical symptom.Clinical symptomAbsence–Presence+ Open table in a new tab Presence or absence of clinical symptoms associated with diseases in the clinical trial is as shown in Table 1. Body temperature is described numerically, and if the maximal temperature is less than 37 °C, the case is judged to be one without fever. Additionally, symptoms resulting from the underlying diseases are not assessed. Midstream urine samples in males and catheterized urine (bladder urine) samples in females are preferred, but midstream urine can also be used in females when obtained according to the procedures described below. Catheterized urine should be used for re-examination in cases where there is some doubt about results from midstream urine. The method used to obtain the urine sample should be clearly recorded. The route and site of indwelling should be noted for patients with an indwelling catheter. Principally, a closed drainage system is used, and urine is collected by inserting a needle into the tube, but in open drainage systems, urine flowing out of the catheter is collected directly after disinfecting and cleaning the tip of the catheter. Procedures for midstream urine sampling •Ambulatory males. Wet a cotton sponge or gauze with cold, warm, or soapy water and give it to the patient in the outpatient clinic.Procedures1.Wash hands.2.Expose the penis.3.Retract the foreskin from over the glans to expose the glans in the case of phimosis.4.Wipe the glans thoroughly with the wet cotton sponge or gauze.5.Hold the cup for collecting the urine sample without touching the inside of the cup, void the initial stream of urine into the toilet, and collect only midstream urine in the cup. Void any remaining urine into the toilet without putting it into the cup.Essential points•Use a new cup if the patient touches the inside of the cup or drops it on the floor.•Have the patient tell the doctor when he has difficulty in retracting the foreskin, or when the position of the external urethral orifice is abnormal.•If there are problems with the urine sample upon medical examination, collect another urine sample after wiping the penis clean. Otherwise, collect catheterized urine.•Use a lidded cup if possible, covering the cup immediately after micturition. •Ambulatory females. Wet a cotton sponge or gauze with cold, warm, or soapy water and give it to the patient in the outpatient clinic.Procedures1.Wash hands.2.Lower underpants or panties sufficiently or remove them completely.3.Open both legs as wide apart as possible.4.Open the labia with one hand and keep them open until the urine sample has been obtained.5.Wipe the area around the urethral orifice (external urethral orifice) thoroughly with the wet cotton sponge or gauze.6.Hold the cup for collecting the urine sample without touching the inside of the cup, void the initial stream of urine into the toilet, and collect only midstream urine in the cup. Void any remaining urine into the toilet without putting it into the cup.Essential points•Let the patient confirm the urethral orifice by herself and have her wipe slowly from the front to the back.•Patients with a lot of pubic hair or who are obese should wipe the area around the orifice especially thoroughly with the wet cotton sponge or gauze.•Use a new cup if the patient touches the inside of the cup or drops it on the floor.•Use a lidded cup if possible, covering the cup immediately after micturition. •Bedridden patients. Catheterized urine is preferable to midstream urine for both male and female bedridden patients. Midstream urine samples should be obtained in basically the same way as in ambulatory patients.ProceduresMale1.Expose the penis.2.Place a bedpan under the patient.3.Retract the foreskin from over the glans to expose the glans in the case of phimosis.4.Wipe the glans thoroughly with the wet cotton or gauze.5.Void the initial urine into the bedpan.6.Collect midstream urine in the cup, being careful to keep the penis from touching the cup.Female1.Remove the underpants or panties completely.2.Place a bedpan under the patient.3.Open both legs and knees as wide apart as possible.4.Open the labia with one hand and keep them open until the urine sample has been taken.5.Wipe the area around the urethral orifice (external urethral orifice) thoroughly with the wet cotton sponge or gauze.6.Void the initial urine into the bedpan.7.Collect midstream urine in the cup. Acute uncomplicated cystitis that is considered of bacterial origin. 1.Sex: Women (subgroup analysis shall be performed separately for postmenopausal cases).2.Clinical symptoms: dysuria, frequent urination, urgency, suprapubic pain. However, patients without any such symptoms of cystitis within 4 weeks of this episode are excluded.3.Pyuria: Patients meeting any of the following criteria before initiation of treatment. Prescribed equipment using non-centrifuged urine: ≥10 WBCs/μl. Counting chamber method using non-centrifuged urine: ≥10 WBCs/μl. Urinary test strip that uses non-centrifuged urine (based on esterase activity determination): Positive. (However, because of occasional false negatives, reconfirmation of negative cases by another method is advisable.) Microscopy of urinary sediment: ≥5 WBCs/high-power field (hpf). Bacterial count: Viable bacterial count before initiation of medication of <105 CFU/mL (midstream urine and catheterized urine). The following bacterial species are targeted. In cases where bacterial strains other than the following are isolated at ≥105 CFU/mL, adoption or rejection shall be judged after examining the details.Staphylococcus sp.Enterococcus faecalisStreptococcus agalactiaeEnterobacteriaceae The dosage period is from a single dose to 7 days depending on the characteristics of the drug. 1.Timing Assessment shall be made 5–9 days after completion of therapy and 21–28 days after the start of therapy. However, the primary endpoint shall be the primary efficacy 5–9 days after completion of therapy.2.At 5–9 days after completion of therapy (assessment of cure) (Table 2, Table 3, Table 4, Table 5)(1)Microbiological outcome (Table 2).Assessments are categorized as ‘‘Eradication’’ or “Failure’’ according to Table 2.Also, ‘‘Failure’’ is divided into subclassifications of “Persistence’’ or ‘‘Undeterminable’’. (Table 3).(2)Clinical outcome (Table 4)Assessments are categorized as ‘‘Cure’’ or ‘‘Failure’’ according to Table 4.(3)Primary efficacy (primary endpoint) (Table 5)Assessments are categorized as ‘‘Response’’ or ‘‘Failure’’ according to Table 5.Table 2Microbiological outcome for acute uncomplicated cystitis (Assessment of cure).EradicationThe number of bacteria per bacterial strain of all urinary tract pathogens isolated before administration is <104 CFU/mLFailureThe number of bacteria per bacterial strain of any urinary tract pathogens isolated before administration is ≥104 CFU/mL, or changes/additions of antimicrobial agents Open table in a new tab Table 3Subclassification of ‘‘Failure’’ for acute uncomplicated cystitis.PersistenceThe number of the same isolated bacterial strain as that before administration is ≥104 CFU/mLUndeterminableNot judged as “Persistence”, comprising changes/additions of antimicrobial agents Open table in a new tab Table 4Clinical outcome for acute uncomplicated cystitis (Assessment of cure).CureAll clinical symptoms disappeared, or the degree of symptoms improved to the level before the development of infectionFailureAny subjective symptoms remain, symptoms absent at assessment of cure are exacerbated, or changes/additions of antimicrobial agents Open table in a new tab Table 5Primary efficacy endpoint for acute uncomplicated cystitis (Assessment of cure) (Primary endpoint).ResponseBoth the bacteriological outcome is Eradication and clinical outcome is CureFailureEither the bacteriological or clinical outcome or both are Failure Open table in a new tab 3.At 21–28 days after the start of therapy. (Assessment of recurrence) (Table 6, Table 7, Table 8).Table 6Bacteriological outcome for acute uncomplicated cystitis (Assessment of recurrence).EradicationThe number of bacteria per bacterial strain of all urinary tract pathogens isolated before administration is <104 CFU/mLFailureThe number of bacteria per bacterial strain of any urinary tract pathogens isolated before administration is ≥104 CFU/mL, or changes/additions of antimicrobial agents Open table in a new tab Table 7Clinical outcome for acute uncomplicated cystitis (Assessment of recurrence).CureAll clinical symptoms disappeared, or the degree of symptoms improved to the level before the development of infectionFailureAny subjective symptoms remain, symptoms absent at assessment of cure are exacerbated, or changes/additions of antimicrobial agents Open table in a new tab Table 8Primary efficacy endpoint for acute uncomplicated cystitis (Assessment of recurrence).ResponseBoth the bacteriological outcome is Eradication and clinical outcome is CureFailureEither the bacteriological or clinical outcome or both are Failure Open table in a new tab Cases determined bacteriologically as ‘‘Eradication’’ 5–9 days after completion of therapy shall be targeted.(1)Bacteriological outcome (Table 6)Assessments are categorized as ‘‘Eradication’’ or “Failure’’ according to Table 6.(2)Clinical outcome (Table 7)Assessments are categorized as ‘‘Cure’’ or ‘‘Failure’’ according to Table 7.(3)Assessment of recurrence (Table 8)Assessments are categorized as ‘‘Response’’ or ‘‘Failure’’ according to Table 8. Acute uncomplicated pyelonephritis that is considered bacterial and that is tested within 3 days of onset of the current episode. 1.Sex: Women (subgroup analysis shall be performed separately for postmenopausal cases).2.Clinical symptoms: Fever of 37.5 °C or higher, lumbago, flank pain, or costophrenic angle knocking pain. Cases of acute uncomplicated pyelonephritis within 4 weeks before this episode are excluded.3.Pyuria: Patients with pyuria meeting any of the following criteria before medication. Prescribed equipment using non-centrifuged urine: ≥10 WBCs/μl. Counting chamber method using non-centrifuged urine: ≥10 WBCs/μl. Urinary test strip using non-centrifuged urine (based on esterase activity determination): Positive (Because of occasional false negatives, reconfirmation of negative cases by another method is advisable.) Microscopy of urine sediment: ≥5 WBCs/hpf. Bacterial count: Viable bacterial count before initiation of medication of <105 CFU/mL (midstream urine and catheterized urine). Bacterial strains: The following strains shall be targeted. In cases where bacterial strains other than the following are isolated at ≥105 CFU/mL, adoption shall be judged after examining the details.Staphylococcus sp.Enterococcus faecalisStreptococcus agalactiaeEnterobacteriaceae Limited to 14-day administration, depending on the characteristics of the drug. 1.Timing Assessment shall be made 5–9 days after completion of therapy and 21–28 days after the start of therapy. However, in clinical trials of a parenteral drug, when the parenteral drug is switched to an oral drug after administration of the parenteral drug, the assessment of efficacy is assessed at the end of administration of the parenteral drug (about 4–6 days after the start of therapy). Primary endpoint is determined to be a primary efficacy endpoint on days 5–9 after the end of administration. However, in clinical trials of parenteral drugs, when the parenteral drug is switched to an oral drug after administration of the parenteral drug, a primary efficacy endpoint at the end of administration of the parenteral drug (about 4–6 days after the start of therapy) is added to the primary endpoint.2.5–9 days after completion of therapy and at the end of administration of a parenteral drug (about 4–6 days after the start of therapy) when the parenteral drug is switched to an oral drug after administration of the parenteral drug in clinical trials of parenteral drugs. (Assessment of cure) (Table 9, Table 10, Table 11, Table 12).(1)Microbiological outcome (Table 9, Table 10).Assessments are categorized as ‘‘Eradication’’ or “Failure’’ according to Table 9.Also, ‘‘Failure’’ is divided into subclassifications of “Persistence’’ and ‘‘Undeterminable’’ (Table 10).(2)Clinical outcome (Table 11)Assessments are categorized as ‘‘Cure’’ or ‘‘Failure’’ according to Table 11.(3)Primary efficacy endpoint (primary endpoint) (Table 12).Assessments are categorized as ‘‘Response’’ or ‘‘Failure’’ according to Table 12.Table 9Microbiological outcome for acute uncomplicated pyelonephritis (Assessment of cure).EradicationThe number of bacteria per bacterial strain of all urinary tract pathogens isolated before administration is <104 CFU/mLFailureThe number of bacteria per bacterial strain of any urinary tract pathogens isolated before administration is ≥104 CFU/mL, or changes/additions of antimicrobial agents Open table in a new tab Table 10Subclassification of ‘‘Failure’’ for acute uncomplicated pyelonephritis.PersistenceThe number of the same isolated bacterial strain as that before administration is ≥104 CFU/mLUndeterminableNot judged as “Persistence”, comprising changes/additions of antimicrobial agents Open table in a new tab Table 11Clinical outcome for acute uncomplicated pyelonephritis (Assessment of cure).CureAll clinical symptoms disappeared, or the degree of symptoms improved to the level before the development of infectionFailureAny subjective symptoms remain, symptoms absent at assessment of cure are exacerbated, or changes/additions of antimicrobial agents Open table in a new tab Table 12Primary efficacy endpoint for acute uncomplicated pyelonephritis (Assessment of cure) (Primary endpoint).ResponseBoth the bacteriological outcome is Eradication and clinical outcome is CureFailureEither the bacteriological or clinical outcome or both are Failure Open table in a new tab 3.At 21–28 days after the start of therapy. (Assessment of recurrence) (Table 13, Table 14, Table 15).Table 13Bacteriological outcome for acute uncomplicated pyelonephritis (Assessment of recurrence).EradicationThe number of bacteria per bacterial strain of all urinary tract pathogens isolated before administration is <104 CFU/mLFailureThe number of bacteria per bacterial strain of any urinary tract pathogens isolated before administration is ≥104 CFU/mL, or changes/additions of antimicrobial agents Open table in a new tab Table 14Clinical outcome for acute uncomplicated pyelonephritis (Assessment of recurrence).CureAll clinical symptoms disappeared, or the degree of symptoms improved to the level before the development of infectionFailureAny subjective symptoms remain, symptoms absent at assessment of cure are exacerbated, or changes/additions of antimicrobial agents Open table in a new tab Table 15Primary efficacy endpoint for acute uncomplicated pyelonephritis (Assessment of recurrence).ResponseBoth the bacteriological outcome is Eradication and clinical outcome is CureFailureEither the bacteriological or clinical outcome or both are Failure Open table in a new tab Cases in which assessments of primary endpoint are determined to be “Response” on days 5–9 after the end of therapy and at the end of administration of a parenteral drug (about 4–6 days after the start of therapy) when the parenteral drug is switched to oral drug after parenteral administration in clinical trials of parenteral drugs are examined.(1)Bacteriological outcome (Table 13)Assessments are categorized as ‘‘Eradication’’ or “Failure’’ according to Table 13.(2)Clinical outcome (Table 14)Assessments are categorized as ‘‘Cure’’ or ‘‘Failure’’ according to Table 14.(3)Assessment of recurrence (Table 15)Assessments are categorized as ‘‘Response’’ or ‘‘Failure’’ according to Table 15. Patients with expected clinical cure by antimicrobial therapy of complicated urinary tract infection due to indwelling catheter (pyelonephritis, cystitis). 1.Clinical symptoms: fever, dysuria, urgency, frequency, suprapubic pain, lumbar pain, discomfort on micturition, lower abdominal discomfort, and sensation of residual urine caused by urinary tract infection.2.Pyuria: Patien