wagenlehner - urinary tract infections epidemiology and...
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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
- Standort Gießen -Justus-Liebig-Universität Gießen, Germany
(Head: Prof. Dr. W. Weidner)
Urinary tract infections epidemiology and management strategies
Florian M.E. WagenlehnerNAUGI 2015
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Urogenital Infections
� UTI
� Prostatitis
� Urethritis – STD
� Epididymitis
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Flores-Mireles 2015
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Flores-Mireles 2015
Bacterial Spectrum of urinary tract infections
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Brumbaugh AR et al. Exp rev vaccines 2012
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Total Antibiotic Consumption
G. Kahlmeter et al., JAC, 2003
% E. coli resistant ≥ 4 antibiotics
Def
ined
Dai
ly D
ose
(DD
D)
per
100
inha
bita
nts/
day
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UTI is a driver ofantibiotic resistance
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Van Boeckel et al. Lancet Inf Dis 2014
Global antibiotic consumption 2010
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Global antibiotic consumption 2000 to 2010
Van Boeckel et al. Lancet Inf Dis 2014
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Superorganism Human
The Human Microbiome(Nature, 2012)
100 % human
10 % human90 % microbial
birth
deathDomann 2014
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Substance Effect on collateral flora Compartment
Aminoglycoside ESBL ↑ -
Carbapenems MRSA ↑ ↑ ↑VRE ↑ ↑ ↑FQr P. aeruginosa ↑ ↑ ↑S. maltophilia ↑ ↑
intestinal floraanaerobic activity
Cephalosporines ESBL ↑ ↑ ↑C. difficile ↑ ↑
intestinal flora
Fluorchinolones ESBL ↑ ↑MRSA ↑ ↑C. difficile ↑ ↑
intestinal floraskin flora
Fosfomycin - -
Nitrofurantoin - -
Penicillines ESBL ↑ intestinal flora
Pivmecillinam - -
Sulfonamides ESBL ↑ intestinal flora
Epidemiological effects of antibiotics
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The dilemma of empiric therapy
Nordberg P et al. Antibacterial drug resistance 2004
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Point of care susceptibility testing –Isothermal Microcalorimetry
Braissant O et al.JCM 2014
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Global Prevalence Study on health care -associated Infections in Urology (GPIU -study)
F. Wagenlehner, T. Bjerklund Johansen – GPIU Study coordinators
� 2003 – 2014� 56 countries� 21.230 patients
http://gpiu.esiu.org/
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Global and regional resistance rates of uropathogens from urological patients
BLI, β-lactamase inhibitor; TMP/SMX, Trimethoprim/sulfamethoxazole.Tandogdu Z, et al. GPIU study group. World J Urol. 2013.
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Increasing frequency of Urosepsis
GPIU study group. Tandogdu Z, et al. ECCMID 2014
Simple Urosepsis = 76%Severe Urosepsis/ septic Shock = 24%
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„New“ Antibiotics in severe UTI
• Ceftolozan/ Tazobactam vs. Levofloxacin – filed
– 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
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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
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Primary and Secondary Efficacy Analysis at TOC
NI marginCeftolozane/tazobactam
n/N (%)
Levofloxacinn/N (%)
Percentagedifference (95% CI)
306/398 (76.9) 275/402 (68.4) 8.5 (2.3 to 14.6)
284/341 (83.3) 266/353 (75.4) 8.0 (2.0 to 14.0)
95% CI
PP population
mMITT population
Ceftolozane/tazobactam – levofloxacin (difference [%])
n/N (%) n/N (%) (95% CI)
320/398 (80.4) 290/402 (72.1) 8.3 (2.4 to 14.1)
294/341 (86.2) 274/353 (77.6) 8.6 (2.9 to 14.3)
-10 -5 5 10 150
PP population
mMITT population
20
-10 -5 5 10 150 20Microbiologicaleradication
-10 -5 5 10 150
PP population
mMITT population
20
Clinical cure n/N (%) n/N (%) (95% CI)
366/398 (92.0) 356/402 (88.6) 3.4 (-0.7 to 7.6)
327/341 (95.9) 329/353 (93.2) 2.7 (-0.8 to 6.2)
Composite curePrimary end point
Wagenlehner F, et al. Lancet 2015.
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Composite Response by Baseline Diagnosis (MITT at TOC)
Ceftolozane/Tazobactam
Levofloxacin Diff.(95% CI)
Overall 306/398 (76.9%) 275/402 (68.4%) 8.5 (2.3 to 14.6)
Pyelonephritis 259/328 (79.0%) 240/328 (73.2%) 5.8 (-0.7 to 12.3)
cLUTI 47/70 (67.1%) 35/74 (47.3%) 19.8 (3.7 to 34.6)
Wagenlehner F, et al. Lancet 2015.
Pat
ient
s w
ith c
ure
(%)
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Per-pathogen Microbiological Eradication (mMITT at TOC)Key Gram Negative Pathogens
Wagenlehner F, et al. Lancet 2015.
Pat
ient
s w
ith e
radi
catio
n (%
)
0
10
20
30
40
50
60
70
80
90
100
C/T
Levofloxacin
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Outcomes in Key Subgroups (mMITTat TOC)
Ceftolozane/Tazobactam
Levofloxacin 95% CI
Composite cure 38/61 (62.3%) 20/57 (35.1%) 9.2 to 42.9
Clinical cure 55/61 (90.2%) 42/57 (73.7%) 2.6 to 30.2
Levofloxacin-resistant pathogensESBL-producing pathogens
Ceftolozane/Tazobactam
Levofloxacin 95% CI
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.
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„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
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Alternative strategies in UTI
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Flores-Mireles 2015
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Beerepot MA et al. J Urol 2013
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George NJR, 1999
Vaginal epithelium glykogen
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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)
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Flores-Mireles 2015
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Urine Microbiome profile (16S rRNA Gen Sequencing)
Pearce M M et al. mBio 2014
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Urine Microbiome profile (16S rRNA Gen Sequencing)
Pearce M M et al. mBio 2014
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Urine Microbiome profile (16S rRNA Gen Sequencing)
Pearce M M et al. mBio 2014
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Flores-Mireles 2015
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Mulvey MA et al., 2000
Uropathogenic E. coli at uroepithelial cells
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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
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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
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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
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Cranberry vs. Plazebo≥ 1 Infection Follow up
Jepson et al. Cochrane 2012
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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
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Flores-Mireles 2015
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Flores-Mireles 2015
Uncomplicated cystitis
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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
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Bishop BL. Nature 2007
Exocytosis of fusiform vesicles by Forskolin
Control
Forskolin
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Do we need to treat the bacteria at all in benign
infection?
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Symptomatic treatment (ibuprofen) vs antibiotics (ciprofloxacin) for uncomplicated UTI
Bleidorn J et al. 2010 BMC Medicine
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No benefit of antibiotic therapy in Diabetics with Asymptomatic Bacteriuria (ABU)
Harding G et al. NEJM 2002
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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
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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
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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
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Can we influence host susceptibility?
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� Extract from 18 UPEC strains� Oral administration� 6 RCTs� Three meta-analysis
OM-89, an Oral Immunostimulant Against Recurrent UTI
SPC Swissmedic 2006
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OM-89 in mice
Lee SJ, WJU 2006
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OM-89 in mice
Lee SJ, WJU 2006
Control E. coli LPS E. coli LPS + Urovaxom
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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)
0.610.82 0.71
0.46
0.15
1.14
1.8
1.461.35
0.71
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Frey Tammen Schulman Magasi Pisani
UT
I p
er
pa
tient
Clinical studies
OM-89Placebo
6 months duration 5 double-blind placebo controlled studies
Bauer (12 months f-up)
0.84
1.28
p = 0.0026, two-sided ANOVA
12 months duration 1 double-blind placebo controlled study
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OM-89S vs. placebo/ nitrofurantoinKaplan-Meier analysis
Time to next symptomatic UTI (days)Wagenlehner F et al. Urol Int 2015
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� Extract from 10 uropathogenic strains� E. coli� P. vulgaris� K. pneumoniae� M. morganii� E. faecalis
� Intramuscular administration� no RCT
� Intravaginal administration� 3 RCTs
Intramuscular Immunostimulant (StroVac ®)Intravaginal Immunostimulant (Solco -Urovac ®)
Against Recurrent UTI
Naber K et al. 2010
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Vaginal Immunostimulation% patients with UTI
Author/ application Immuno-stimulant
Placebo Sig. RR
Hopkins 2007/ Weeks 0, 1, 2 75.0% 84.0% n.s. 89.3%
Hopkins 2007/ Weeks 0, 1, 2, 6, 10, 14 53.8% 84% <0.05 64.1%
Uehling 1997/ Weeks 0, 1, 2 98.4% 100.0% n.s. 98.4%
Uehling 2003/ Weeks 0, 1, 2 88.9% 88.9% n.s. 100.0%
Uehling 2003/ Weeks 0, 1, 2, 6, 10, 14 44.4% 88.9% <0.01 50.0%
Total 78.9% 89.7% <0.05 88.0%
Naber K et al. 2010
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Beerepot MA et al. J Urol 2013
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Prevention of recurrent cystitis in womenEAU Guidelines 2015
Grabe M et al. EAU Guidelines on Urological Infections 2015 www.uroweb.org
1) counseling and behavioral modification, i.e. avoidance of risk factors
2) Non-antimicrobial measures
3) Continuous or post-coital antimicrobial prophylaxis should be considered only in women in whom non-antimicrobial measures have been unsuccessful
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Vaccination
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Brumbaugh AR et al. Exp rev vaccines 2012
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Catheter associated UTI
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Complicated UTI
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0 10 20 30 40 50 60 70
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
Cat
het
ers
The time taken for 18 different types of catheters to block in the bladder model infected with Proteus mirabilis .
Time (h)
Bard Hydrogel/Silver Coated Latex
Bard Hydrogel Coated LatexWarne Silicone Treated LatexWarne Teflon Coated LatexSimpla Silicone Coated Latex
Rusch Ultrasil Silicone Coated LatexBard Teflon Coated Latex
Eschmann Folatex Silicone Treated LatexEschmann Silicone Treated Latex - Tiemann
TipBard Silicone Coated LatexRusch Silkolatex SL Cath (Silver impregnated)Rusch Simplastic
Rusch Silikon 100
Simpla All SiliconeEschmann Silicone Treated Latex - Stewart Tip
Rusch Simplastic - Whistle Tip
Bard All SiliconeEschmann Folatex S All Silicone
Prevention of complications of bacteriuria encrustation
N.S.Morris B.J.of Urology 1997.80,58-63
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Symptomatic catheter-associated UTI(Latex vs. Silver vs. Nitrofurazone)
Silver vs. Latex
Nitrofurazone vs. Latex
Pickard R. Lancet, 380, 2012, 1927 - 1935
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Polyurethane and heparin -coated urinary stents in vivo
C.Riedl:Int.J.of Antim. Agents 2002P.Tenke Int.J.of Antim. Agents 2004
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Urease inhibitors
• Acetohydroxamic acid (AHA)– Side effects
• Benzimidazole– Inactivate ATPase systems
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Flores-Mireles 2015
?
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Non antimicrobialtreatment of the host in
severeUTI?
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Protective effect of mitochondria -targeted antioxidant (SkQR1)
Plotnikov E Y et al. PNAS 2013;110:E3100-E3108
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Protective effect of mitochondria -targeted antioxidant (SkQR1)
Plotnikov E Y et al. PNAS 2013;110:E3100-E3108
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Antimicrobial stewardship
• Surveillance of antibiotic usage• Adherence to guidelines
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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
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Summary
• UTI frequent• UTI driver of antibiotic resistance• New antibiotics in severe UTI• Niche antibiotics in benign UTI• Alternative strategies to antibiotic
treatment in benign UTI• Treatment of the host