EAU-Guidelines for the Treatment of Uncomplicated UTI

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1 EAU-Guidelines for the Treatment of Uncomplicated UTI Kurt G. Naber Technical University of Munich, Germany Sao Paulo, 26 May 2007

2 Gäubodenvolksfest - Straubing

3 EAU Guidelines for the Management of Urinary and Male Genital Tract Infections Board of the European Society of Infection in Urology/EAU: Naber KG, Germany (Chairman) Bjerklund Johansen TE, Norway Botto H, France Bishop M, UK Cek M, Turkey Grabe M, Sweden Lobel B, France Palou J, Spain Tenke P, Hungary European Association of Urology 2006

4 Prevalence of Uncomplicated Cystitis 20-30% of the adult women experience one or more episodes of dysuria per year intercourse seems to be the cause of 75-90% of all urinary tract infections in sexual active women Sunford (1975); Nicolle et al (1982); Leibovici et al (1987)

5 Relative Risk for Symptomatic Urinary Tract Infections days with intercourse days diaphragm and spermicide used in the past 7 days Hooton et al (1996) N Engl J Med 335:

(526) NETHERLANDS (46) GERMANY (357) AUSTRIA (107) POLAND (125)

8 SITES DISTRIBUTION ARESC AUSTRIA: 3 RUSSIA (447) BRASIL: 6 FRANCE:10 GERMANY: 7 HUNGARY: 4 ITALY: 4 NETHERLANDS: 2 BRASIL (522) FRANCE (526) NETHERLANDS (46) GERMANY (357) AUSTRIA (107) POLAND (125) HUNGARY (106) POLAND: 6 RUSSIA: 10 SPAIN (680) ITALY (342) SPAIN: 9 TOTAL: 61

9 AETIOLOGY of uncomplicated UTI E. coli 76.3% ARESC N (%) E.coli 2484 (76.3%) S. saprophyticus 117 (3.6%) K.pneumoniae 114 (3.5%) P. mirabilis 101 (3.1%) E.faecalis 100 (3.0%) Citrobacter 33 (1%) Enterobacter 26 (0.8%) P.aeruginosa 7 (0.2%) 3254 uropathogens Other ENT 144 (4.4%) other G+ 121 (3.7%)

12 Acute Uncomplicated Cystitis Aims of Treatment rapid disappearance of clinical symptoms reduction of morbidity prophylaxis of reinfections these aims can be satisfactorily realized by short-term antibiotic therapy

13 Advantages of the Short-term Therapy good compliance low costs few adverse events low impact on periurethral, vaginal and rectal flora persistent bacteriuria after 2-3 days may indicate involvement of parenchyma or underlying complicating factor

14 Oral Treatment Options of Acute Uncomplicated Bacterial Cystitis in Adult Premenopausal, Non-Pregnant Women* Substance Dosage Duration LE GR Reference Ciprofloxacin 250mg bd 3 days 1b A Iravani 1995, Vogel 2004 CiproXR 500mg od 3 days 1b A Henry 2002 Enoxacin 200mg bd 3 days 1b B* Backhouse 1987 Fleroxacin 400mg SD 1b B* Iravani 1993 Fleroxacin 200mg od 3 days 1b B* Iravani 1995 Fosfomycin Trom 3000mg SD 1a A Lecomte 1997, Minassian 1998 Gatifloxacin 200mg od 3 days 1b A Richard 2002, Naber 2004 Gatifloxacin 400mg SD 1b A Richard 2002, Naber 2004 Levofloxacin 250mg od 3 days 1b A Richard 1998 Lomefloxacin 400mg od 3 days 1b B* Neringer 1992, Nicole 1993 Nitrofurantoin mg fd 5-7 days 1b A Goettsch 2004 Nitrofurantoin 100mg SR bd 7 days 1b A Spencer 1994 Norfloxacin 400mg bd 3 days 1b A Inter-Nordic 1988, Piippo 1990 Ofloxacin 200mg bd 3 days 1b A Block 1987, Hooton 1989/91 Pefloxacin 800mg SD 1a B* Naber 1994 Pivmecillinam 200mg bd 7 days 1b A Nicolle 2000/02, Menday 2002 Pivmecillinam 400mg bd 3 days 1b B* Nicolle 2000/02, Menday 2002 Rufloxacin 400mg SD 1b B* Jardin 1995 Trimethoprim 200mg bd 5-7 days 1a A Warren 1999, Goettsch 2004 Trimethoprim 200mg bd 3 days 1b B* Gossius 1985 TMP-SMX 160/800mg bd 3 days 1a A Gossius 1984, Hooton 1999

15 Meta-analysis of 15 comparative trials with Fosfomycin Trometamol in cystitis treatment Fosfomycin Trometamol SD Comparison treatments* 3 7 days Statistical significance All studies Short term eradication % 655/ % 653/ % NS Long term eradication % 556/ % 524/ % P<0.05* Adverse events % 90/ % 80/ % NS Amoxicillin, Amociclav, Cephalexin, Cotrimoxazole, Nitrofurantoin, Norfloxacin, Ofloxacin, Pefloxacin, Pipemidic acid, Trimethoprim From Lecomte 1997 (modified)

16 Treatment of Acute Uncomplicated Cystitis in Premenopausal, Otherwise Healthy Women Pathogens Escherichia coli (70-90%) Less frequent Staphylococcus saprophyticus Klebsiella spp. Proteus mirabilis Initial Empiric Therapy Fosfomycin Trometamol: 1 day Pivmecillinam: 7 days Nitrofurantoin: 5-7 days *Trimethoprim + SMX: 3 days *Trimethoprim: 5-7 days *Fluoroquinolon: 3 days Treatment Duration Days *consider local E. coli resistance EAU guidelines, update 2006

17 Empiric Therapy with TMP-SMX in 544 Premenopausal, Non-Pregnant Women with Acute Uncomplicated Cystitis Therapy TMP-SMX 160/800mg bid for 5 days TMP-SMX sensitive (S) pathogens 384/544 (71%); E. coli 77% TMP-SMX resistant (R) pathogens 160/522 (29%); E. coli 81% Microbiologic cure Visit 2 (5-9d): S = 266/335 (86%) R = 64/151 (42%) Clinical cure Visit 2 (5-9)d: S = 293/335 (88%) R = 81/151 (54%) Adverse events: S = 59/353 (16.7%) R = 23/149 (15.4%) Conclusion: Unacceptable Rates of Failures in R-Pathogens R. Raz et al. 41th ICAAC, Chicago, Sept 2001; # L-1350

18 History 49-year old female patient Recurrent cystitis for about 2 years, ca. 2x/year, never febrile Since 30 June 2005 dysuria Therapy with TMP/ SMZ 160/800mg bid for 3 days Since 3 July 2005 increasing pain in both CVA Since 5 July 2005 fever upto 40.2 C Hospital admission PE040456

19 PE040456

20 21-year old female patient 2 weeks ago: History - Dysuria, frequency and painful micturition: - Therapy: ciprofloxacin 100 mg bid for 3 days improvement 1 week ago: - Moderate flank pain 3 days ago: - Therapy: ciprofloxacin 250mg bid 1 day ago: - Fever 38.9 C Hospital admission GK250985

21 GK250985

22 Management of Acute Cystitis short-term therapy persistence of symptoms: revisit after 3 days, otherwise revisit after 1-2 and 4-6 weeks cure no other examination or therapy failure urologic investigation reinfection rare often prophylaxis EAU guidelines 2006

23 Acute Uncomplicated Cystitis with Increased Risk of Failure after Short Term Therapy Risk Factors -male - pregnancy (?) - post menopause (?) - recurrent UTI in childhood (?) - symptoms > 7 days - recent antimicrobial therapy - recent intervention of the urinary tract - diabetes mellitus

24 Three vs Seven Day Treatment of Symptomatic Uncomplicated UTI in Women > 65 years with Ciprofloxacin 250 mg bid Study completed Females (>65y) Bacterial eradication - 2 days after therapy Clinical improvement/cure - 2 days after therapy Adverse events per subject* - up to 5 days - up to 9 days Relapse at 6 weeks after X 3-day 93 98% 98% 0.9* 1.2* 15% 14% 7-day 90 93% 92 % 1.6* 2.1* 13% 18% Exclusion: Reinfection diabetes at mellitus, 6 w after indwelling X catheter, abnormal renal function, recent use of antibiotics, signs of pyelonephritis. E. coli 170 (71.0%); K. pneumoniae 29 (15.8%) *p<0.001 Vogel T. et al 2004 CMAJ 170:

25 Acute Uncomplicated Cystitis in Elderly Women Females (n=140) yrs with symptomatic uncomplicated cystitis No history of ruti, cfu >10*5/ml; E. coli (72,1%) Treatment Fosfomycin trometamol: 3g SD Results (7d post X) Clinical Micobiological Adverse Events (n=140) Evaluable patients: 126 Cure + Improvement: 90 % + 6 % = 96 % Eradication/patient: Total (n=126) = 87 % E. coli (n=91) = 99 % In 15 patients In 2 patients moderate allergic AE were drug related Rudenko & Dorofeyer 2006 GIMMOC 10:3-10

26 Treating UTI during Pregnancy ( approved by FDA USA ) Drug Use in Pregnancy Penicillins B - e.g. Pivmecillinam Cephalosporins - B Fosfomycin B Nitrofurantoin B Fluoroquinolones C TMP C, D first trim SMX C, D last trim B : animal studies do not demonstrate or human studies do not confirm fetal risk C : animal studies indicate adverse fetal effects not refuted adequately in human studies D : positive evidence exists of human fetal risk

27 UTI / Bacteriuria in Pregnancy Success rate after 1 month Fosfomycin Trometamol (n=153) 3g single dose 93 % Pipemidic Acid (n=138) 400 mg bid for 7-days 90 % Zinner 2001 Chemotherapy 36 (suppl 1) 50-52

28 Antimicrobial Prophylaxis of Recurrent Cystitis* daily/weekly reduced doses of antimicrobials postcoital reduced dose of an antimicrobial self short term therapy immune therapy (eg. Urovaxom, Strovac) hormonal replacement (local) unspecific prophylaxis (eg. urine acidification, cranberry juice) probiotics *in women with >3 episodes per year

29 Antibiotics for preventing ruti in non-pregnant women* Antibiotic versus Placebo Cinoxacin 250 mg/24h 1/23 Placebo 17/22 Martens 1995 Cinoxacin 500 mg/24h 8/21 Placebo 17/19 Martorana 1984 Cinoxacin 500 mg/24h 2/15 Placebo 4/13 Schaeffer 1982 Cinoxacin 500 mg/24h 1/20 Placebo 8/21 Scheckler 1982 Norfloxacin 200 mg/24h 0/11 Placebo 10/13 Nicolle 1989 Norfloxacin 200 mg/24h 4/18 Placebo 13/17 Rugendorff 1987 Nitrofurantoin 100 mg/24h 1/13 Placebo 5/6 Stamm 1980 Nitrofurantoin 50 mg/24h 3/25 Placebo 15/25 Bailey 1971 Cephalexin 125 mg/24h 1/20 Placebo 13/23 Gower 1975 TMP/SMX 40/200/24h 1/13 Placebo 5/7 Stamm 1980 TMP/SMX 40/200/PC 2/16 Placebo 9/11 Stappleton 1990 Total Verum 24/195 Placebo 116/177 Recurrence rate 12.3% 65.5% Relative risk 0.21 (0.13;0.34) *patients (n/n) with at least one microbiological recurrence during prophylaxis vs total patients; PC-postcoital. Albert X, Huertas I, Pereiro II, Sanfelix J, Gosalbes V, Perrota C. Cochrane Database Syst Rev. 2004;(3):CD

30 Fosfomycin Trometamol (FT) Study completed Females (18-65y) Mean age (y) Mean BMI E. coli (acute episode) Dosage Duration Prophylaxis in recurrent UTI* FT % 3g every 10 d 6 months Placebo % 3g every 10 d 6 months Patients with an acute episodes during 6 months prophylaxis days 11 (7.0%) 108 (75.0%) Total number of lower UTI/patient year days p<0.001 * two weeks after clearence from acute episode. Rudenko et al 2005 Drug Res 7: 420-7

31 Prophylaxis of Recurrent Cystitis daily or after intercourse Nitrofurantoin mg/day Trimethoprim mg/day TMP-SMZ 40/200 mg/day or trice/ week Fosfomycin trometamol 3g every 10 days in case of break through infection (?) Norfloxacin 200 mg/day Ciprofloxacin 125 mg/day in case of pregancy Cephalexin mg/day EAU guidelines 2006

32 Prophylaxis of Recurrent Cystitis in Non-Pregnant Women Verum versus Placebo Patients with microbiological recurrence during prophylaxis Antimicrobial 24/195 (12.3%) Urovaxom 93/231 (40.3%) Placebo 116/177 (65.5%) Placebo 122/222 (55.0%) Reduction: 81.2% Reduction: 16.7% Albert et al 2004 Cochrane Database Syst Rev.(3):CD Bauer et al 2005 Eur Urol. 47:

33 Recurrent* UTIs: Postmenopausal Women number estriol 0.5 mg/g vaginal cream once each night for 2 weeks followed by twice-weekly for 8 months placebo women (total) completed 8 months of study patients with bacteriuria 8 27 episodes of bacteriuria symptomatic asymptomatic 12 8 s 2 s UTI per patient and year 0.5 s 5.9 Raz et al (1993) NEJM 329: *3 or more microbiologically confirmed symptomatic UTI s = significant

34 Cranberry Juice vs. Placebo* in 153 elderly females (mean 78.5 years) 40 Cranberry Placebo Bacteriuria (%) Base Months *each day 300 ml; mean urine-ph 6.0 vs. 5.5 Avorn et al (1994), JAMA 271:

35 Asymptomatic Bacteriuria/Candiduria > 10 5 cfu/ml in two urine cultures (>24 hrs apart) Treament indicated during pregnancy before urological interventions and in renal transplant patients (relative indication) Treatment not indicated, e.g. diabetes mellitus bacteriuria/candiduria in patients with indwelling catheters or splints

36 Harding et. al, NEJM 2002 Antibiotic Therapy in Diabetics with Asymptomatic Bacteriuria Verum versus Placebo

37 Fosfomycin Trometamol vs Cefuroxime Axetyl Treatment of asymptomatic bacteriuria (two specimens >10^5 cfu/ml) in 2nd trimester of pregnancy Dosage Study completed Mean age (years) Mean gestational age (weeks) Pathogens E. coli E. faecalis Staphylococci Eradication (after 7 days) Adverse events FT 3g SD /44 2/44 1/ % 1x allergic skin rash CA 250mg bid/5 days /40 1/40 1/ % 2x vulvovaginal moniliasis Persistence: 3x S. saprophyticus; 2x E. faecalis Bayrak et al 2006 Int Urogynecol

38 Uncomplicated Cystitis (I) high number of patients involved high impact on daily activity high impact on quality of life short-term antibiotic therapy is the treatment of choice

39 Uncomplicated Cystitis (II) Choice of best drug depends on - epidemiology - drug properties Any improvement on treatment management will have an high impact on - health care - health economics

TMP/SMZ DS Ciprofloxacin Norfloxacin Ofloxacin Cefadroxil * 30 Amoxicilin 86* 19 25

TMP/SMZ DS Ciprofloxacin Norfloxacin Ofloxacin Cefadroxil * 30 Amoxicilin 86* 19 25 Evidence-Based Evaluation and Treatment of UTI UTI Prevalence Leslee L. Subak, MD Associate Professor Obstetrics, Gynecology & RS Epidemiology & Biostatistics University of California, San Francisco 50%