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

Urogenital Infections

� UTI

� Prostatitis

� Urethritis – STD

� Epididymitis

Flores-Mireles 2015

Flores-Mireles 2015

Bacterial Spectrum of urinary tract infections

Brumbaugh AR et al. Exp rev vaccines 2012

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

UTI is a driver ofantibiotic resistance

Van Boeckel et al. Lancet Inf Dis 2014

Global antibiotic consumption 2010

Global antibiotic consumption 2000 to 2010

Van Boeckel et al. Lancet Inf Dis 2014

Superorganism Human

The Human Microbiome(Nature, 2012)

100 % human

10 % human90 % microbial

birth

deathDomann 2014

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

The dilemma of empiric therapy

Nordberg P et al. Antibacterial drug resistance 2004

Point of care susceptibility testing –Isothermal Microcalorimetry

Braissant O et al.JCM 2014

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/

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.

Increasing frequency of Urosepsis

GPIU study group. Tandogdu Z, et al. ECCMID 2014

Simple Urosepsis = 76%Severe Urosepsis/ septic Shock = 24%

„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

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

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.

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

(%)

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

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.

„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)

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

OM-89S vs. placebo/ nitrofurantoinKaplan-Meier analysis

Time to next symptomatic UTI (days)Wagenlehner F et al. Urol Int 2015

� 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

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

Beerepot MA et al. J Urol 2013

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

Vaccination

Brumbaugh AR et al. Exp rev vaccines 2012

Catheter associated UTI

Complicated UTI

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

Symptomatic catheter-associated UTI(Latex vs. Silver vs. Nitrofurazone)

Silver vs. Latex

Nitrofurazone vs. Latex

Pickard R. Lancet, 380, 2012, 1927 - 1935

Polyurethane and heparin -coated urinary stents in vivo

C.Riedl:Int.J.of Antim. Agents 2002P.Tenke Int.J.of Antim. Agents 2004

Urease inhibitors

• Acetohydroxamic acid (AHA)– Side effects

• Benzimidazole– Inactivate ATPase systems

Flores-Mireles 2015

?

Non antimicrobialtreatment of the host in

severeUTI?

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

treatment in benign UTI• Treatment of the host