JUSTUS- LIEBIG UNIVERSITÄT GIESSEN Clinic for Urology, Pediatric Urology and Andrology Clinic for Urology, Pediatric Urology and Andrology Universitätsklinikum Gießen und Marburg GmbH - Standort Gießen - Justus-Liebig-Universität Gießen, Germany (Head: Prof. Dr. W. Weidner) Urinary tract infections epidemiology and management strategies Florian M.E. Wagenlehner NAUGI 2015
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JUSTUS- LIEBIG
UNIVERSITÄTGIESSEN
Clinic for Urology, Pediatric Urology and Andrology
Clinic for Urology, Pediatric Urology and AndrologyUniversitätsklinikum Gießen und Marburg GmbH
– F. Wagenlehner, O. Umeh, J. Huntington, D. Cloutier, I. Friedland, J. Steenbergen, G. Yuan, M.J. Yoon, R. Darouiche. Efficacy and Safety of Ceftolozane/Tazobactam versus Levofloxacin in the Treatment of Complicated Urinary Tract Infections (cUTI)/ Pyelonephritis in Hospitalized Adults: Results from the Phase 3 ASPECT. Lancet 2015
• Ceftazidim/ Avibactam vs. Doripenem – Phase 3
• RPX2014/ RPX 7009 vs. Piperacillin/ Tazobactam – Pha se 3
• S-649266 vs. Imipenem – Phase 2
• Finafloxacin vs. Ciprofloxacin – Phase 2
• Plazomicin vs. Levofloxacin – Phase 2
• Mono Sulfactam / BAL30072 – Phase 1
Ceftolozane/tazobactam4.5g/day vs. Levofloxacin 750mg/day
All randomized (N = 1083)(ITT population)
Ceftolozane/tazobactamITT population (n = 543)
LevofloxacinITT population (n = 540)
MITT(n = 534)
mMITT(n = 402)
CE (n = 370)
ME (n = 353)
MITT(n = 534)
mMITT (n = 398)
CE (n = 356)
No study drug received
(n = 9)
No study drug received
(n = 6)
No baseline pathogen(n = 132)
Not per protocol (n = 32)
No urine culture at
TOC(n = 17)ME
(n = 341)
No baseline pathogen(n = 136)
Not per protocol (n = 42)
No urine culture at
TOC(n = 15)
CE, clinically evaluable; ITT, intent-to-treat; ME, microbiologically evaluable; MITT, modified intent-to-treat; mMITT, microbiological modified intent-to-treat; TOC, test of cure.Wagenlehner F, et al. Lancet 2015
Composite cure 60/100 (60.0%) 44/112 (39.3%) 7.2 to 33.2
Clinical cure 90/100 (90.0%) 86/112 (76.8%) 3.1 to 22.9
Wagenlehner F, et al. Lancet 2015.
„Niche“ antibiotics in benign infections – uncomplicated cystitis (UC)
Women with acute UC� absence of fever, flank pain etc� able to take oral medication
Consider alternative diagnosis ,e.g. PN or cUTI & treat accordingly
First line antimicrobials
Nitrofurantoin MC 100mg bid 5 daysor
Fosfomycin trometamol 3g SDor
Pivecillinam 400mg bid 5 days
No
Yes
Alternatives
TMP-SMX 160/800mg bid 3 daysIf resistance of E. coli < 20%
orFluoroquinolones
resistance high in some areasor
Beta-lactamslower efficacy than other agents,
requires close follow-up
Wagenlehner F et al. S3 Leitlinie HWI 2011
Alternative strategies in UTI
Flores-Mireles 2015
Beerepot MA et al. J Urol 2013
George NJR, 1999
Vaginal epithelium glykogen
postmenopausal UTI: Estriol
5,9
0,5
0,5 mg/d 2 weeks, 0,5 mg/2x week for 8 months
Infections/ Patient year
Raz u. Stamm, New Engl J Med 1993
Estriol (n=50)Placebo (n=43)
Flores-Mireles 2015
Urine Microbiome profile (16S rRNA Gen Sequencing)
Pearce M M et al. mBio 2014
Urine Microbiome profile (16S rRNA Gen Sequencing)
Pearce M M et al. mBio 2014
Urine Microbiome profile (16S rRNA Gen Sequencing)
Pearce M M et al. mBio 2014
Flores-Mireles 2015
Mulvey MA et al., 2000
Uropathogenic E. coli at uroepithelial cells
Uropathogens fimbriae
B. Wullt EAU 2014
Fimbriae (P and Type 1) are small hair-like bacterial organells that attach to the uroepithelium
P fimbria is expressed by moststrains in pyelonephritis and sepsis
Type 1 fimbriae is by some authors considered important for lower UTI
Mulvey MA et al., 2000
Typ 1 Pilus - FimH Adhesins
Uropathogens fimbriae
Fimbriae (P and Type 1) are small hair-like bacterial organells that attach to the uroepithelium
P fimbria is expressed by moststrains in pyelonephritis and sepsis
Type 1 fimbriae is by some authors considered important for lower UTI
Cranberry vs. Plazebo: cell adhesionUPEC G1722 Adhesion on T24 Bladder epithelial cells
(A) 250 ml Placebo(B) 250 ml Cranberry(C) 750 ml Placebo(D) 750 ml Cranberry
Di Martino et al. WJU 2006
Plazebo
Plazebo Cranberry
Cranberry
In vitro data support that cranberries (vaccinium macrocarpon) contain a tannin called proanthocyanidins (PAC) – which inhibits P-fimbrial adhesion of E. coli to uro-epithelial cells
Cranberry vs. Plazebo≥ 1 Infection Follow up
Jepson et al. Cochrane 2012
Peroral D-mannose as prevention of recurrent UTI a non blinded randomized controlled trial
Kranjcec et al. 2014
Development of small-molecule inhibitors called mannosides that bind to FimH with affinities 200,000- fold
greater than mannose
Flores-Mireles 2015
Flores-Mireles 2015
Uncomplicated cystitis
E. coli within mouse bladders after 3 days AB treatment
Blango M G , and Mulvey M A Antimicrob. Agents Chem other. 2010;54:1855-1863
CFU/g
Bishop BL. Nature 2007
Exocytosis of fusiform vesicles by Forskolin
Control
Forskolin
Do we need to treat the bacteria at all in benign
infection?
Symptomatic treatment (ibuprofen) vs antibiotics (ciprofloxacin) for uncomplicated UTI
Bleidorn J et al. 2010 BMC Medicine
No benefit of antibiotic therapy in Diabetics with Asymptomatic Bacteriuria (ABU)
Harding G et al. NEJM 2002
Group A (n=312) – ABU not treatedGroup B (n=361) – ABU treated
Cai T et al. CID 2012
A
B
Asymptomatic bacteriuria (ABU) in young women with recurrent UTI: Antibiotic therapy harms
Aymptomatic bacteriuria protects against UTI
p= 0.00431
E. coli 83972PBS
Per
cent
age
recu
rren
ce fr
ee p
atie
nts
0.0
0
.2
0
.4
0
.6
0
.8
1
.0
Time (days)0 50 100 150 200 250 300 350
Sundén et al. J Urol 2010
Reprogramed host transcription
Bacterial adaptation
Symptomatic infection
Asymptomatic carriage
ABUTLR4
ABUIRF3
Decreased host response
T
RNAPol II
Supressed host transcription
E. coli 82972wt
T
RNAPol II
T
RNAPol II
IFNPRR
Wullt B et al., EAU 2014
Can we influence host susceptibility?
� Extract from 18 UPEC strains� Oral administration� 6 RCTs� Three meta-analysis
OM-89, an Oral Immunostimulant Against Recurrent UTI
SPC Swissmedic 2006
OM-89 in mice
Lee SJ, WJU 2006
OM-89 in mice
Lee SJ, WJU 2006
Control E. coli LPS E. coli LPS + Urovaxom
Results from Placebo Controlled Clinical Studies
Frey CH et al. Urol Int 1986;41:444-446 Magasi P et al. Eur Urol 1994 ;26 ;137-40Tammen H. Br J Urol 1990;65 :6-9 Schulman CC et al. J Urol 1993 ; 150 :917-21 Bauer H.W. et al, Eur Urol 2005;47:542-548 Pisani E et al. OMpharma data on file 1992 (quoted in Chiavaroli C et al. BioDrugs 2006;20 :141-9)
Protective effect of mitochondria -targeted antioxidant (SkQR1)
Plotnikov E Y et al. PNAS 2013;110:E3100-E3108
Protective effect of mitochondria -targeted antioxidant (SkQR1)
Plotnikov E Y et al. PNAS 2013;110:E3100-E3108
Antimicrobial stewardship
• Surveillance of antibiotic usage• Adherence to guidelines
Adherence to EAU Guideline on prophylactic preoperative antibiotics reduced Resistance
Time period 2008 – 2010Pre-intervention
2011 – 2013Post-intervention
Patients 2,619 3,529
Adherence to EAU guideline n.e. 87%
Defined Daily Doses/ 100 patient days 2.1 1.8
- Aminoglycosides 1.2 0.6*
- Fluoroquinolones 3.1 0.9*
Postoperative infections 4.5% 5.1%
E. coli resistance
- Aminoglycosides 18.3% 11.2%*
- Fluoroquinolones 32.3% 19.1%*
- Piperacillin/tazobactam 9.1% 5.4%*
Antibiotic costs and treatment of infections 123,000 € 67,000 €*
Cai T et al. EAU congress 2015*p<0.05
Summary
• UTI frequent• UTI driver of antibiotic resistance• New antibiotics in severe UTI• Niche antibiotics in benign UTI• Alternative strategies to antibiotic