This document discusses urinary tract infections (UTIs), including: 1. Definitions, epidemiology, etiology, pathogenesis, clinical manifestations, diagnosis, and treatment principles of UTIs. 2. UTIs can be classified as upper (e.g. pyelonephritis) or lower (e.g. cystitis) depending on infection location. Escherichia coli is the most common causative agent. 3. Diagnosis involves urine culture and microscopy to detect bacteria and white blood cells. Treatment depends on infection type and culture sensitivities.

1. Urinary Tract Infection Department of Nephrology,the First Affiliated Hospital , Sun Yat-sun University Qiongqiong Yang [email_address]

2. Growth of >10 5 organisms per milliliter from a properly collected midstream “clean-catch ” urine sample Definitions Dysuria frequency urgency

3. Anatomic categories: upper urinary tract infection ： Pyelonephritis lower urinary tract infection ： Cystitis, urethritis Categories urethra Female Urinary System bladder ureter kidney uterus

4. Epidemiological categories: Catheter-associated Community-acquired Symptomatic or not (Dysuria, frequency , urgency ) Symptomatic Asymptomatic Categories

5. EPIDEMIOLOGY General population 0.91% incidence Women 2.05% Nonpregnant adult woman 5.0% Pregnant women 7% Elderly women 10% Elderly men (>50yrs) 7.0% infant 1.0% School Girls 1-2% School Boys 0.03% *Data from 30,196 women 1 st Affiliated Hospital of SunYat sen Uni

6. EPIDEMIOLOGY USA: Episodes of acute cystitis in female : 11% per year Approximately 50%-60% of adult women report that they have had a UTI at some time during their life. Acute cystitis : 36 million pts per year (18-75y); cost 16 hundred million $.

7. Etiology Microorgnisma: Bacteria, fungi, virus, Chlamydia trachomatis, Mycoplasma The most common agents: the gram-negative bacilli. Escherichia coli : 70% of acute uncomplicated UTI Staphylococcus saprophyticus :5%-15% in young women Proteus mirabilis, Klebsiella species, enterococci or other uropathogens

8. Pathogenesis Sources of infection Predisposing factor Local and systemic host defense mechanisms Pathogenicity of the stain Ascending infection Hematogenous infection Lymphathic way

9. Bacteria gain access to bladder via urethra, or follow by ascent from bladder to renal parenchyma. Sources of infection Ascending infection bladder urethre

10. Sources of infection Ascending infection Staphylococcal species: the vaginal introitus, and distal urethra Facilitated by the factors such as sexual intercourse, contraceptive (spermicide) entrance Enteric G(-) organisms: colonize on the rectal introitus, the perurethral skin, and distal urethra rectal introitus Vaginal introitus Dital urethra

11. Gender and sexual activity: Bacteriuia in women ： very common The female urethra: colonization with colonic G negative bacilli Anatomy ： Proximity to the anus ； Short length (-4cm) ； Its termination beneath the labia ( 唇） Facilitating factors ： Sexual intercourse （ causing the introduction of bacteria into bladder ） Bacteriuia in Male ： urethral obstruction by prostatic hypertrophy, bacterial prostatitis Male <50 yrs old without history of sexual rectal intercourse : uncommon Predisposing factor

12. Obstruction: ( Hydronephrosis) tumor, stricture, stone, prostatic hypertrophy vesicoureteral reflux, Neurogenic bladder dysfunction Predisposing factor Hydronephrosis Dilation of ureter Obstruction Retrograde pyelograpy

13. Use of instruments ： cystoscopy ， urethral catheterization or indwelling urethral catheter Malformation and structural abnormalities : posterior urethral valve dysfunction Urethra or periurethral infection ： genital infection ， bacterial prostatitis Renal parenchyma lesion ： DN ， Polycystic KD Poor immunity ： use of immunosuppressive agents ， kidney transplantation Defect of local mucous membrane of urethra defense ability Predisposing factor

14. Flushing effects of urine voiding Antibacterial effects of urine: low pH, high osmolarity, high urea concentration Antibacterial of the bladder mucosa: Secretion of organic acids and antibodies eg. IgA Antibacterial of prostatic fluid Barrier effect of sphincter of urethra Local and systemic host defence mechanisms

15. Bacterial virulence factors E coli: specific O,K, and H serogroups

16. urethral stimulate symptom dysuria (burning or discomfort on urination), frequency Infectious or noninfectious stimulate Decreased volume of bladder Disorder of cystic nerve function Clinical Manifestation

17. Clinical Manifestation Cystitis acute pyelonephritis Dysuria, frequency, urgency obvious obvious Fever, shaking chills none showed Costovertebral angles tenderness /sensitive to percussion none showed WBC mostly normal increased pathogenic bacterium Escherichia coli （ 75%) coagulated negative staphylococcus （ 15% ） Escherichia coli 、 bacillus proteus 、 Klebsiella

18. Clinical Manifestation Asymptomatic bacteriuria Uncomplicated UTIs Complicated UTIs Recurrent UTIs Reinfection : different strains, >1month, Cystitis Relapse: the same strain, <1month, pyelonephritis

19. Complication Bacteremia or Septicemia Papillary necrosis DM, pregnancy, urinary obstruction Hematuria, pain in the flank or abdomen, chills and fever, ARF Necrosis tissue is passed in the urine Ring shadow on pyelography Perinephric abscess

20. Laboratory test Pyuria Bacteriuria Other ： WBC (leukocytosis) ， Erythrocyte sedimentation rate (ESR) ， intravenous pyelography(IVP) ， C-reactive protein.

21. Pyuria Urinary sediment of cleaning urine specimen : ≥5 wbc/HFP ， ≥ 0.4 × 10 6 /hr; ≥ 1.0 × 10 6 /12hr ， WBC esterase test （ + ） WBC casts -Pyelonephritis High sensitivity , but lower specificity （ 70% ） Leukorrhea contamination sterile pyuira : unusual infection such as tuberculosis, fungi, chlamydia/mycoplasma infection interstitial nephritis

23. Bacteriuria Suprapubic bladder aspirates : bacteria growth on the culture dish （ qualitative culture ， Golden standard ） Voided midstream “clean-catch” urine sample Qualitative culture Colony counts （ Quantitative culture ） ≥ 10 5 CFU [colony forming unit] /ml G+ ≥10 3 CFU /ml 10 4 -10 5 CFU /ml suspicious , need reexamination  10 4 CFU /ml contaminative significant

24. Unspun, clean-catch urine specimen Gram’s stain Bacteria can be seen /HFP  10 5 /ml(95%) Both sensitivity and specificity are 92% Midstream “clean-catch” urine sediment  20 bacteria /HP Bacteriuria

25. Chemical examination Nitrites test (Griess Test): nitric acid nitrous acid ( G （ - ） bacilli ) sensitivity : 70.4%, specificity : 99.5% E nteribacillus ： + Enterococcus ， staphylococci ， streptococcus faecalis ： - Urine dipsticks ： leukocyte esterase ， Griess Test Screening test

26. Gram negative bacilli. Escherichia coli Gram positive cocci in chains. Enterococcus faecalis Gram positive cocci Staphylococcus saprophyticus Gram positive budding yeasts and large pseudohyphae. Candida albicans

27. False bacteriuria should be excluded Urine samples were contaminated by leucorrhea, etc. Urine sample was put at room temperature for more than 1 hr before inoculated. Technical errors .

28. False negative in Urine culture Use of antibiotics 7 days before culture. Frequency: Urine stayed in the bladder for less than 6 hours; Water diuresis or recent voiding Disinfectant contaminating into urine sample Anaerobe ， chlamydia ， fungi or other microorganism infection.

29. Other examination WBC (leukocytosis) Intravenous pyelography(IVP) Recurrent UTIs ， complicated UTIs （ stone ）， Recurrent pyelonephritis ， unusual bacteria infections ， a history of UTI in pregnancy ， a history of childhood infections ， Male with UTI ， Painless hematuria Ultrasonic examination Renal tubule function Vesicoureteral reflux test during voiding forbid to perform at acute phase!

30. Diagnosis Patient with bacteriuria : diagnosed as UTI. Colony counts ≥10 5 CFU ／ ml （ midstream “clean-catch” urine cultures ） . For asymptomatic pts, urine cultures should be done twice, Each time colony counts ≥10 5 CFU ／ ml with same bacteria. G+ colony counts ≥ 10 3 CFU /ml Bacteriuria

31. Diagnosis UTI upper UTI acute pyelonephritis lower UTI Symptoms and signs, pathogenic bacteria, tubule function and leukocyte cast cystitis Systemic toxic symptoms ： T >38℃ ， WBC  ， costovertebral angle tenderness/sensitive to percussion leukocyte cast Recurrent within 4 weeks after ending the treatment Complicated with obstruction or malformation, etc Unusual bacteria: Bacillus proteus Renal dysfunction IVP showing abnormal image . Pyelonephritis

32. Review of 3 days therapy No symptoms , pyuria, bacteriuria Noninfectious Urethral syndrome Without bacteriuira With symptoms Without symptoms Yes No Without bacteriuira With bacteriuira Woman with urethral stimulate symptom 3 days antibiotics therapy （ TMP-SMZ 2 # Bid / Ofloxacin 0.2g Bid ） Urinalysis and urine bacteria culture Cystitis (cured) Symptoms relapse with pyuria and bacteriuria pyelonephritis (occult ) pyuira pyelonephritis Urethral syndrome caused by chlamydia trachomatis 7 days later 1W~1M

33. Differential Diagnosis Systemic infection Diseases chronic pyelonephritis: pyelography or ultrasonic examination Cortex scars and kidney pelvis /calices deformed Renal size: asymmetric Tubuler dysfunction Renal tuberculosis Urethral syndrome

34. Renal tuberculosis The following Conditions should be suspected : Chronic urethral stimulate symptoms Useless of antibiotics therapy Urine bacteria culture negative Pyuria, Aciduria Evidence of extrarenal tuberculosis: Epididymis, spermatic cord or prostate tuberculosis

35. Renal tuberculosis Confirmed diagnosis ： (any one of the following three conditions can make a diagnosis ） 1. Clinical manifestation+ urine tubercle bacillus culture positive. 2. X-Ray indicated typical manifestation of renal TB. 3. Cystoscopy showed typical lesion of cystitis TB.

36. Urethral syndrome Infectious Urethral syndrome: Acute urethritis mycoplasma or chlamydia Azithromycin(1g in a single oral dose) , Doxycycline(100mg twice a day), Ofloxacin Noninfectious Urethral syndrome: without pyuria and bacteriuria No antimicrobial treatment May related to dryness of the urethral and vaginal mucosa in postmenopausal, estrogen-deficient women, psychological status such as anxiety

37. Treatment Principles Treatment for different types of UTIs

38. Principle(1) Urine culture: Who: Except in acute uncomplicated cystitis in women When: before empirical treatment is begun. How to use the culture results: antimicrobial sensitivity testing should be used to further direct therapy.

39. Principle(2) Factors predisposing to infection should be identified and corrected if possible. obstruction and calculi In general, uncomplicated lower UTIs respond to short courses of therapy(3 days), while upper UTIs require longer treatment(14 days).

40. Principle(3) Antibiotics selection: First chose antibiotics should be effective to G- bacilli TMP and Fluoroquinolone can be used empirically as first line drug. The presence of antibiotic-resistant strains should be suspected: in pts with repeated infections, instrumentation, or recent hospitalization, and antimicrobial sensitivity testing should be used .

41. Principle(4) Therapeutic judgments: Relief of clinical symptoms does not always indicated bacteriologic cure. pt should be follow up at 2w and 6w after cessation of treatment. A cure : resolution of symptoms and elimination of bacteriuria. A failure: Presence of bacteriuria with or without symptoms .

42. Principle(5) Therapeutic judgments: Recurrent infections should be classified as Relapse: the same-strain occurring within 2 weeks of the end of therapy. ( an unresolved upper tract focus of infection ; persistent vaginal colonization) Reinfection: recurrences > 2 weeks after the cessation of therapy with a new strain.

43. Treatment for different types of UTIs Acute uncomplicated Cystitis in women Acute uncomplicated pyelonephritis Recurrent UTIs UTIs in Pregnancy UTIs in Male Catheter-associated UTIs Asymptomatic bacteriuria UTIs in Children

44. Acute uncomplicated Cystitis in women Common organisms: E coli or Staphylococus saprophyticus single-dose therapy: Take the antibiotics for only one time with a relatively large dose(SMZ （ SMX400g ， TMP80mg ） 6 pills draught / Ofloxacin 0.6g draught). more frequently relapse 3-days therapy: Eradicate vaginal and rectal flora colonization with E coli TMP-SMZ 2 # Bid / Ofloxacin 0.2 Bid The best choice is 3 days therapy !

45. Acute uncomplicated Cystitis in women The short-term therapy should not be used Diabetes pts with the immunosuppressive therapy previous infections due to antibiotic-resistant organisms UTI symptoms for >7 d UTI in pregnancy age>65yrs males with UTI ( urologic abnormalities or prostatic involvement) Use of diaphragm 7- to 14 day regimen

46. CASE I 32 year-old woman History: dysuria , frequency and pain on urination for 2 days gross hematuira for 1 day Physical: (-) Urinalysis: WBC+++ , RBC ++/HPF Lab Data: Isomorphic RBC

47. . Diagnosis Bacteriuria? Gram stain of unspun urine (x1000) showed an inflammatory cell and numerous Gram negative bacilli. Colony counts Escherichia coli ≥10 5 CFU ／ ml （ midstream “clean-catch” urine cultures ） . diagnosed as UTI. Systemic toxic symptoms leukocyte cast cystitis 3 days antibiotics therapy （ TMP-SMZ 2 # Bid / Ofloxacin 0.2g Bid ）

48. Review of 3 days therapy No symptoms , pyuria, bacteriuria Without symptoms Urinalysis and urine bacteria culture Cystitis (cured) 7 days later

49. Acute uncomplicated pyelonephritis Antibiotics therapy: 14 days course Empirical treatment: Fluoroquinolone, the third generation cephalosporin or aminoglycoside Sensitive to G- Bact. (E coli) Less nephrotoxicity and side effects High concentration in renal and urine. Intravenously the first few days, taking orally 72 hrs after fever relieving .

50. Acute uncomplicated pyelonephritis 14 days antibiotics course Acute uncomplicated pyelonephritis Follow up at the 2 nd wk and 6 th wks Failure within 72 hr relapse Relief from symptoms without bacteriuria Cured Change ABs : according to drug sensitive test 6 wks’ ABs therapy predisposing factors: unrecognized suppurative foci calculi urologic disease

51. Recurrent UTIs Bacteriuria reoccurs after cessation of treatment. Reinfection : Cause by a different pathogen, usually occur 6 weeks after drug discontinuance . Cystitis Relapse : the same strain, <2 wks, pyelonephritis About 80% of the recurrent UTIs are reinfection.

52. Recurrent UTIs A short-term antibiotics therapy initially. Follow-up: 1 or 2 wks after cessation therapy. Relief without symptoms ,bacteriuia and pyuria: Reinfection is indicated. The previous treatment was effective. Failure to therapy : Antibiotic-resistant : change to a sensitive ABs for a 7 days therapy Judgments the results of treatment

53. Recurrent UTIs Judgments after therapy with a sensitive ABs for a 7 days therapy : If the antibiotic works well: Reinfection If the antibiotic does not work: Relapse , same strain infection pyelonephritis Prolong treatment to 6 wks. If failed, prolong the course. Check the predisposing factors

54. Recurrent UTIs Recurrent frequently （  2 times in half a year or  3 times in 1 year) long-term ,low-dose antibiotics therapy (bacteriostasis). Daily or thrice-weekly administration of a single dose of nitrofurantoin 50mg, TMP-SMX 80/400mg, ofloxacin 200mg per night after urinate Half a year or may prolong to 1~2 yr

55. History of recurrent UTIs, with UTI symptoms Short-term therapy Review 7 days later effective reinfection sensitive antibiotics Long-term low-dose antibiotics failure effective failure pyelonephritis 6 wks antibiotics therapy Check the complicated factors relapse recurrent UTIs frequencly Antibiotic-resistent Recurrent UTIs

56. Complicated UTIs Presence of the predisposing factors: catheterization, instrumentation, urologic anatomic or functional abnormalities, stone, obsrtuction, immunosuppression, renal disease, or diabetes. Hospital-acquired bacteria: E coli, klebsiella, Proteus, Serratia, pseudomonas, enterococci, and staphylococci. Antibiotic-resistent

57. Complicated UTIs Empirical antibiotic therapy: Broad-specturm Imipenem A penicillin or cephalosporin PLUS an aminoglycoside, or ceftriaxone or ceftazidime Selected on the antimicrobial sensitivity pattern. 10-21 days Follow-up cultures 2-6 wks after cessation of therapy.

58. Removal of catheter Short course of antibiotcs If the catheter cannot be removed: Asymptomatic bacteriuia should be ignored. The pt develops symptoms or in high risk of developing bacteremia: Replacement of the catheter Systemic antibiotic Changing the drainage way if necessary (suprapubic cystotomy). Catheter-Associated UTIs

59. UTIs in Pregnancy Asymptomatic bacteriuria /Acute cystitis All pregnacy women should be screened for asymptomatic bacteriuria during first trimester (4%-7%). 7 days of antibiotics therapy The incidence rate of premature delivery 、 low birth weight will increase if without treatment. Antibiotics: low toxicity such as cephalosporin, Ampicillin , Amoxicillin.

60. UTIs in Pregnancy Acute pyelonephritis Parenteral antibiotic therapy cephalosporin, or extended-spectrum penicillin. Urine culture should be performed to ensure cure, and repeated monthly until delivery. UTIs in Pregnancy Recurrent infection : continuous low-dose prophylaxis with nitrofurantoin.

61. Asymptomatic bacteriuria Antimicrobial therapy is unnecessary in the Elderly pts. Antimicrobial therapy is necessary: High-risk pts with neutropenia, renal transplants, obstruction, or other complicating conditions Preschool children 7 days of oral antibiotics therapy initially longer-term therapy(4-6 wks) in high-risk pts persistent asympomatic bacteriura Monitoring without further treatment

62. Prognosis Uncomplicated UTIs : Complete resolution of symptom (>90%) rarely progress to renal function impairment and chronic renal disease. Complicated UTIs: develop to chronic pyelonephritis difficult to cure unless correcting the predisposing factors.

63. Prevention Drink more water Personal hygiene: pudendum cleaning for female pts, redundant prepuce cleaning for male pts. Avoiding using instruments as possible, and strictly following aseptic manipulation if necessary. Vesicoureteral reflux: To establish a habit that void once again.

64. Prevention Women with frequent symptomatic UTIs (  3 per yr): Long term administration of low-dose Abs Avoid spermicidal use void soon after intercourse recurrent UTIs related to intercourse: The single dose of Abs can be used after sexual intercourse.

65. Take Home Messages Bacteruia and diagnosis of UTI Predisposing factors Complication of UTI Principles of therapy ,cystitis , and acute pyelonephritis

66. Thanks ！