AUA 2019 Uro Infection PDF

030IC:
Uro-Genital Tract Infections: Emerging Threats and

Clinical Guidelines
Saturday, May 4, 2019

7:30 – 9:30a.m.
Faculty
Daniel Arthur Shoskes, MD – Course Director
Florian Wagenlehner, MD
Kurt G. Naber, MD, PhD
JUSTUS- LIEBIG
UNIVERSITÄT
GIESSEN
Prof. Dr. F.M.E. Wagenlehner Prof. Dr. K.G. Naber Daniel Shoskes MD, MSc, FRCS(C)
Director Clinic for Urology, Assoc. Prof. of Urology Professor of Urology
Pediatric Urology and Andrology Department of Urology Director, The Novick Center for Clinical
Justus-Liebig-Universität Gießen Technical University Munich, and Translational Research
Germany Germany Director, Center for Men’s Health
Glickman Urological and Kidney Institute
Cleveland Clinic
Infections of the urogenital tract

AUA instructional course 2019
AUA instructional course 2019 - Chicago
1) Introduction (Wagenlehner)
2) Resistance and FQ warnings (Naber)
3) Uncomplicated UTI (Wagenlehner)
4) Management of recurrent UTI (Naber)
5) Periinterventional prophylaxis, focus transrectal prostate biopsy
(Wagenlehner)
6) Acute, chron bacterial prostatitis, CPPS (Shoskes)
7) Complicated (incl catheter assoc.) UTI, Urosepsis (Wagenlehner)
8) Sexually transmitted infections (Shoskes)
9) Novel antibiotics in UTI (Naber)
10) Q&A
Introduction
Wagenlehner
Conflict of Interest Disclosure
•I have the following potential conflict(s) of
interest to report:
•Consultancy fees and study support (third-
party funding) from Achaogen, Astellas,
AstraZeneca, Bionorica, Calixa
Pharmaceuticals, Cerexa Pharmaceuticals,
Cubist Pharmaceuticals, Janssen, LEO Pharma,
MSD, Pfizer, Rempex Pharmaceuticals, Rosen
Pharma, Shionogi, and Vifor Pharma.
The history of life
Ingested bacterium Ingested bacterium

Animals
becomes mitochondrium becomes chloroplast
Plants
Fungi
Common ancestor of all higher life forms Protozoan
App. 2 billion years
Lokiarchaea
Archaea
Bacteria
Die Zeit 2015

Superorganism human
100 % human birth
10 % human
The Human Microbiome 90 % microbial
(Nature, 2012)
death
Domann 2014
Human Microbiota and Metabolome
Human Microbiome Project, Nature 2012 2

Classification of UTI
Cystitis
Uncomplicated UTI Pyelonephritis Complicated UTI
Recurrent UTI
Catheter-associated UTI
Low risk High risk

UTI in men
Urosepsis
Bonkat G et al. 2018 EAU guidelines infection

Resistance and FQ warnings
Naber
M. Sundquist and G. Kahlmeter (Sweden)
S. Takahashi and T. Muratani (Japan)
Antimicrobial resistance of
uropathogens is increasing
worldwide
International Consultation on Urogenital Infections, EAU 2010

Deaths per year in 2050
O‘Neill Report on Antibiotic Resistance

Global
Prevalence
Study on Health
Care-Associated
Infections in
Urology
(GPIU Study)
since 2003
http://gpiu.esiu.org
performed by the
European Section
of Urology (ESIU)
and sponsored by
the European
Association of
Urology (EAU)
and
co-sponsered by
many other
Scientific Societies
worlwide http://gpiu.esiu.org/
Global Prevalence Study on health care-associated
Infections in Urology (GPIU-study)
 2003 – 2018
 56 countries
 27.230 patients
http://gpiu.esiu.org/
F. Wagenlehner, Z. Tandogdu, T. Bjerklund Johansen – GPIU Study coordinators
Clinical presentation of HAUTI
Global and Regional Resistance Rates
of E. coli
Cek M et al., WJU 2014

Global and Regional Resistance Rates
of all Pathogens
Cek M et al., WJU 2014

Data obtained from studies published 2009–2014
Zowawi et al. 2015 Nature Review Urology
Mortality ESBL vs. non-ESBL-
producing Enterobacteria
Schwaber, Carmeli 2011 JAC

The Global Threat of
NDM-1 Metallo-  -Lactamases
Distribution of countries in which NDM-1-producing Enterobacteriaceae

have been identified up to September 2010
Jean & Hseuh. Int J Antimicrob Agents. 2011;37:291-5

Global distribution of plasmid-mediated mcr-1 colistin-resistant strains
isolated from environments, foods, animals and humans (11/2015 to 04/2016)
Baron et al 2016 IJAA

Touristing in the far east - up to 80% of travellers
in the far east return with multiresistant
gramnegatives in their gut flora.
WHO Rings Alarm Bells
http://safemedicinesindia.in/innerpage.php?title=World%20Health%20Organisation%20names%2012%20s
uperbugs;%20most%20are%20present%20in%20India
There is a clear
correlation between
Antibiotic
Consumption
and
Antibiotic
Resistance Björn Wullt
Percentage change in antibiotic consumption per capita
2000–2010*, by country
Source: Van Boeckel et al. 2015 (adapted; based on IMS MIDAS)
New Antibacterial Agents Approved by the FDA
Total no. of new antimicrobials
IDSA Public Policy. Clin Infect Dis. 2011;52(Suppl 5):S397-S428.

FDA warnings to use fluoroquinolone antibiotics
8 July 2008. FQs are associated with an increased risk of tendinitis and tendon rupture
and worsening of myasthenia gravis.
This risk is further increased in those over age 60, in kidney, heart, and lung transplant
recipients, and with use of concomitant steroid therapy.
Physicians should advise patients, at the first sign of tendon pain, swelling, or
inflammation, to stop taking the FQs, to avoid exercise and use of the affected area,
and to promptly contact their doctor about changing to a non-fluoroquinolone
antimicrobial drug.
The labels also include warnings about the risks of peripheral neuropathy, which may
be irreversible (FDA’s warning 2013) and central nervous system effects.
Other serious risks associated with FQs are such as cardiac, dermatologic, and
hypersensitivity reactions
26 July 2016. FDA warns that FQs for systemic use are associated with disabling and
potentially permanent side effects of the tendons, muscles, joints, nerves, and central
nervous system that can occur together in the same patient.
20 Dec 2018. FDA warns about increased risk of ruptures or tears in the aorta blood
vessel with FQs in certain patients
12 May 2016. FDA is advising that the serious side effects associated with FQs
generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and
uncomplicated urinary tract infections who have other treatment options. For patients
with these conditions, FQs should be reserved for those who do not have alternative
treatment options.
Should urologists stop prescribing fluoroquinolones?
Gernot Bonkat1, Florian Wagenlehner2
1Chair of the EAU guidelines; 2Chair of the European Section of Infection in Urology (ESIU)
Fluoroquinolones (FQs) are associated with serious side effects (see FDA warnings)
There are four main aspects of misuse of FQs:
I. no indication for FQ therapy (no bacterial infection or inappropriate coverage);
II. extended treatment duration without indication;
III. inappropriate dosage; and
IV. inappropriate use in antimicrobial prophylaxis
Inappropriate prescription of FQs for treatment of uncomplicated UTIs represents a
large fraction of poor prescriptions.
Should urologists stop prescribing fluoroquinolones completely? - NO
FQs have advantageous in the treatment of various infections, such as oral
treatment of complicated UTIs, pyelonephritis, and genital infections, e.g chron.
bacterial prostatitis, epididymitis.
In order to ensure the best level of care for each individual patient urologists should
always consider the serious side effects associated with FQs and discuss with the
patient risk and benefit of each FQ prescription.
Six strategies needed in national antibiotic policies
Center for Disease Dynamics, Economics & Policy. 2015.

State of the World’s Antibiotics, 2015. CDDEP: Washington, D.C.
Uncomplicated UTI
Wagenlehner
Case vignette
• 35-years healthy woman presents with urgency, dysuria,
suprapubic pain, no abdominal pain
• Temperature 37,1°C, Pulse 80/ minute, blood pressure
115/60 mm Hg.
• Leucocytes 9.500 Giga/L, serum-creatinine 1,1 mg/dL.
• Urinanalysis positive for leucocyte esterase and nitrit.
Mod. after Johnson JR, Russo TA, NEJM 2018
2
V. Mouraviev mod. according to Alidjanov J et al. Urol Int 2014
Correlation
catheter urine and
midstream urine
in women
Hooton T et al., NEJM 2013; 369: 1883-1891

Case vignette
suprapubic pain, no abdominal pain
115/60 mm Hg.
• During recent travel to India FQ for diarrhoe.
Mod. after Johnson JR, Russo TA, NEJM 2018
5
MDR after foreign travel
Armand-Levefre et al. 2018

MDR after foreign travel
Persistance in fecal flora
Armand-Levefre et al. 2018

Treatment recommendation uncomplicated cystitis
Bonkat G et al. EAU guidelines 2019

Nitrofurantoin 5 days vs. Fosfomycin SD
16
Huttner A et al., JAMA. 2018; 319:1781-1789

Collateral damage of antibiotics
Substance Effect on collateral flora Compartment
Aminoglycoside ESBL  -
Carbapenem MRSA  intestinal flora
VRE 
FQr P. aeruginosa 
S. maltophilia 
Cephalosporine ESBL  intestinal flora
C. difficile 
Fluoroquinolone ESBL  intestinal flora
MRSA  skin flora
C. difficile 
Fosfomycin - -
Nitrofurantoin - -
Penicillin ESBL  intestinal flora
Pivmecillinam - -
Sulfonamide ESBL  intestinal flora
Ibuprofen (400mg 3xtgl.) vs. Fosfomycin (3g 1x) 3 days
in acute uncomplicated cystitis
Total antibiotic prescriptions
37
Gagyor I. et al., BMJ 2015;351:h6544

CanUTI-7 Study: BNO 1045* t.i.d. (7 days) vs. Fosfomycin SD
N=325 N=334
Wagenlehner F et al. Urol Int. 2018; 101:327-336 *Rosemary, Loveage, Centaury herb
Results
Comparison of mean sum-scores of the ACSS-typical domain
Canephron® N ct
Wagenlehner F et al. Urol Int. 2018; 101:327-336

Pyelonephritis rates: non-antibiotic vs. Antibiotic in acute
uncomplicated cystitis
Study Pyelonephritis (n)
Wagenlehner et al. (2018) CanUTI-7 5 [1,5%](BNO 1045),

BNO 1045 vs. Fosfomycin 1 [0,3%](Fosfomycin)
Gagyor et al. (2015) 5 [2,1%] (Ibuprofen),
Ibuprofen vs. Fosfomycin 1 [0.4%] (Fosfomycin)
Kronenberg et al. (2017) 6 [5%] (Diclofenac),
Diclofenac vs. Norfloxacin 0 [0%] (Norfloxacin)
Case vignette
fever, vomiting, flank pain left side
105/50 mm Hg.
• Urine pH 6.5.
Johnson JR, Russo TA, NEJM 2018
15
Van Nieuwkoop et al. CID 2010
Recommended oral empiric therapy in mild and
moderate uncomplicated pyelonephritis
Bonkat et al. 2019 EAU guidelines

Case vignette
fever, vomiting, flank pain left side
105/50 mm Hg.
• During recent travel to India FQ for diarrhoe.
19
Recommended parenteral empiric therapy in
severe uncomplicated pyelonephritis
Bonkat et al. 2019 EAU guidelines

Management of recurrent UTI
Naber
Recurrent Cystitis
≥ 2 acute episodes in 6 months, or ≥3 infections in 1 year
• Within 3 – 4 months of an initial UTI, 20-30%

women will have a recurrence
• 10-20% women are living with recurrent UTIs
Treatment of acute cystitis is not enough !!!!

Likelihood of recurrences have to be taken in
consideration
Foxman, Am J Med, 2002, 113, 3, 5S-13S

Recurrent UTI (Cystitis)*
Risk factors increasing susceptibility to rUTIs
Behavioural General Urogenital

•Sexual intercourse History of UTI •Incontinence
•Diaphragm use Diabetes mellitus •Urinary obstruction
•Spermicid use Oestrogen deficiency •Sphincter detrusor
•Recent antibiotic use dyssynergia
•Urological surgery
*Definition:
≥2 symptomatic episodes within 6 months or ≥3 symptomatic episodes within 1 year
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
49-year old female patient with history of recurrent UTI
and recent onst of dysuria, fever and flank pain
PE040456
Main risk factors increasing susceptibility to
recurrent infections1-3
Pre-menopausal
• Sexual intercourse
• Use of spermicides
• Different sexual partners
• History of UTI before the age of 15
• Maternal history of UTIs
Post-menopausal
• Estrogens deficiency
• Urinary incontinence
• Pelvic organ prolapse with voiding dysfunction
• Diabetes mellitus type 2
• History of UTI
• Non-secretor status (blood groups) Bought from stock image
1. Nicolle, L.E. Infect Dis Clin North Am, 1997; 2. Foxman, B., et al J Clin Epidemiol, 2001; 3. Hooton, T.M et al. 2010 EAU
Preventative Measures for Recurrent Cystitis
3. Antibiotic
prophylaxis
RUTI
prevention
2. Non
1. Behavioral
Behavioral
modification Antibiotic
modifications
prophylaxis
Tenke P. Urological infections 2011 InTech

Bonkat G, et al. EAU Guidelines on Urological Infections 2018 www.uroweb.org
1. Behavior modifications (SR: weak)
 Fluid intake – around 2 liters/day

 Improve inadequate evacuation habits
 Adequate emptying of the bladder
 Urinate before and after intercourse
 Avoid diaphragm, spermicides and
tampons
Bonkat et al. European Association of Urology Guidelines on Urological Infections 2018

Relative Risk for Symptomatic UTI
days with intercourse days diaphragm and spermicide used

in the past 7 days
0 1 2 3 4
0 1.0 1.4
1 1.4 1.9
2 1.9 2.6 3.8
3 2.6 5.1 7.3
4 3.5 14.1
5 4.8
6 6.6
7 9.0
Hooton et al (1996) N Engl J Med 335:468-474

Nomogram for risk prediction of rUTIs (LUTIRE)
RRP= 0+0+40 +0+40 +50=130≈ 0.6
Cai et al., 2014

3. Antimicrobial Prophylaxis
of Recurrent Cystitis*
• Daily/weekly reduced doses of antimicrobials

• Post-coital reduced dose of an antimicrobial
• Self short-term therapy
*In women with >3 episodes per year
Grabe M, et al. EAU Guidelines on Urological Infections 2014 www.uroweb.org

3. Antimicrobial Prophylaxis of Recurrent Cystitis
Daily or after intercourse

• Nitrofurantoin 50–100 mg/day
• Fosfomycin trometamol 3 g every 10 days
In case of pregnancy
• Cephalexin 125–500 mg/day
• Cefaclor 250 mg/day
Bonkat et al. EAU Guidelines on Urological Infections 2018 www.uroweb.org

The vicious cycle of antibiotic exposure
Side
effects
3. Re-
infection Treatment
1. Antibiotic
exposure failure
Antibiotic
resistance
2. Antibiotic
resistance/
host
microbiota
impairment
Dethelfsen et al. PLoS Biol. 2008;6(11):e280

2. Non-antibiotic prophylaxis
Local Estriol-Therapy
Infections/Patient year
5.9
0.5 mg/day for 2 weeks,
0.5 mg/twice per week for 8 months
0.5
Placebo (n=43) Estriol (n=50)

Raz and Stamm, New Engl J Med 1993 EAU guidelines 2018: GR-weak; LE: 1b)
Probiotics
• Probiotics containing strains L. rhamnosus GR-1, L. reuteri

RC-14, and L. crispatus CTV-05 can be considered for
prevention of recurrent UTI
• Vaginal products containing these strains can be used once
or twice weekly for prophylaxis
• Daily use of oral products containing these strains can
restore the vaginal lactobacilli; they compete with urogenital
pathogens and prevent BV, a condition that increases the risk
of UTI
Mod according to Peter Cadieux and Gregor Reid, ICUD 2010 & EAU guidelines 2018
Urinary Tract Infection Rates by Intervention and
Lactobacillus crispatus CTV-05 Colonization Pattern
Lactin-V
(gelatin capsules;
10*8 CFUs/mL)
or
. placebo vaginal
suppositories
once daily
for 5 d.
Follow up:
at 10 weeks
Stapleton et al 2011 CID 52:1212

Cranberry Products
Cochrane review 2012:

 Total of 24 studies (4473 participants)
 Cranberry products did not significantly reduce the occurrence
of symptomatic UTI overall (RR 0.86, 95% CI 0.71 to 1.04)
 And for any subgroups:
 women with recurrent UTIs (RR 0.74, 95% CI 0.42 to 1.31);
 older people (RR 0.75, 95% CI 0.39 to 1.44);
 pregnant women (RR 1.04, 95% CI 0.97 to 1.17);
 children with recurrent UTI (RR 0.48, 95% CI 0.19 to 1.22);
 cancer patients (RR 1.15 95% CI 0.75 to 1.77); or
 people with neuropathic bladder/spinal injury
(RR 0.95, 95% CI: 0.75 to 1.20)
Jepson RG et al. Cranberries for preventing urinary tract infections (Review) .

The Cochrane Collaboration, Issue 10, 2012. Published by John Wiley & Sons, Ltd
Adhesion Blockers: D-Mannose
Group1
D-Mannose:
2g powder in
200 ml water qd
Group 2
Nitrofurantoin
50mg qd
Group 3
No prophylaxis
Kranjcec et al 2014 World J. Urol. 32:79-84

Immunotherapy, Vaccines
Placebo Controlled Trials with OM-89*
5 Double-blind placebo controlled studies 1 double-blind placebo
controlled study 12-
6 months duration
months duration
OM-89
Placebo
2 1.8 1.28
1.46
1.5 1.35
0.84
UTI per patient
1.14
1 0.82 0.71 0.71
0.61 0.46
0.5 p = 0.0026,
0.15 two-sided ANOVA
0
Frey Tammen Schulman Magasi Pisani Bauer (12 months f-up)
*Uro-Vaxom©
Frey CH et al. Urol Int 1986;41:444-446 ; Magasi P et al. Eur Urol 1994 ;26 ;137-40; Tammen 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)
2. Non-antimicrobial preventive measures
Recommendations supported by medical evidence
Immunoactive prophylaxis OM-89, lyophilized bacterial lysate of 18
strains of E.coli (GR: Strong; LE: 1a – EAU guidelines 2018)
Mean number of episodes of

p<0.00001
• Meta-analysis of 1.0
urinary tract infections

5 double-blind, -39%
placebo
controlled
studies 0.5 0.95
• 6–12 month 0.60
duration
0.0
Placebo Uro-Vaxom®
(n=495) (n=480)
• OM-89 group had significantly fewer UTI than placebo after 6 months
• 39% reduction was observed taken the 12- month of follow-up
Bonkat et al. European Association of Urology Guidelines on Urological Infections 2018

Naber et al. International Journal of Antimicrobial Agents 2009;33:111-19
Adapted from Naber KG et al. Int J Antimicrob Agents. 2009;33(2):111-9
Meta-analysis
Oral Uro-Vaxom
1
Vaginal Urovac
Oral Oestriol
Vaginal Oestriol
Lactobacilli
Cranberries
Acupuncture
Beerepot MA et al. J Urol 2013

Vaccines for the prevention of recurrent urinary tract
infections: New systematic review
OM-89
OM-89
Urovac
ExPEC4V
OM-89
OM-89
OM-89
Urovac
Urovac
OM-89S
(modified)*
When compared to other non-antimicrobial prophylaxis, OM-89 showed greatest reduction in UTI recurrence rate, with
maximal effect seen at 3 months compared with 6 months after initial treatment (RR 0.67 95% CI 0.57-0.78 and RR 0.78
95% CI 0.69-0.88
*OM-89S involved a modified production process, its development stopped in 2015
Aziminia et al. Eur Urol Suppl 2018; 17(2);e327

Oral immunomodulation in 136 individuals
with chronic spinal cord injury for prevention of rUTI
sporadic UTIs (1-2/year)

recurrent UTIs (≥3/year)
Krebs et al. Neurourology and Urodynamics. 2018;1 (retrospective, observational study)

Questions
Which is your preferred management of rUTI ?
1. Antibiotic prophylaxis
2. Cranberries
3. D-Mannose
4. Probiotics
5. Estrogen
6. Immunoprophylaxis
7. Others
Periinterventional prophylaxis,
focus transrectal prostate biopsy
Wagenlehner
Definition of antibiotic
prophylaxis
Short, usually single dose, administration of

an antibiotic substance in normal dosage
prior to start of operation.
ASA physical status
classification
Category Patient condition Risk of complication
1 Normal healthy patient No particular

2 Mild systemic disease No particular
3 Severe systemic disease Risk increase
4 Severe incapacitating systemic disease that Risk increase

is constant threat for life
5 Moribund, not expected to survive without High risk

the operation
WJUrol 2012;30:39-50
Antibiotic prophylaxis for specific
urological procedures

Complications after prostate biopsy
App. 1.000.000 prostate biopsies in USA/ year
Nam RK et al., 2010

ESIU prostate biopsy side study
patients with
Transrectal P-BX 1152/1194 (97%)
Antibiotic prophylaxis 1164/1195 (98%)
FQ based prophylaxis 941/1151 (82%)
Symptomatic UTI 43/876 (5%)

 7x E. coli
 4x Enterococcus sp.
 2x Klebsiella sp.
 2x Pseudomonas sp.
 1x Proteus sp.
 1x Staphylococcus epidermidis
 4x other
Febrile UTI 24/876 (3%)

Hospitalisation 34/876 (4%)
Wagenlehner et al. 2015; EAU congress

case – 65 years old patient
• Outpatient prostate biopsy
• Morbidity:
– Brain infarction; C2-abusus; Hypertension; coronary artery sclerosis
• Prophylaxis: Ciprofloxacin
• Admission with signs of sepsis
• Therapy: Levofloxacin 500 1-0-1
case – 65 years old patient
• Outpatient prostate biopsy
• Morbidity:
– Brain infarction; C2-abusus; Hypertension; coronary artery sclerosis
• Prophylaxis: Ciprofloxacin
• Admission with signs of sepsis
• Therapy: Levofloxacin 500 1-0-1
• Urine culture: E. coli 106/ml
• Resistant: Penicillines, FQ, Cotrimoxazole, Aminoglycosides
Antibiotic prophylaxis vs. no prophylaxis
10 studies
p=0.0005
Pilatz A et al., EAU 2018

Fecal FQ-resistant E. coli as a risk factor for infectious
complications after prostate biopsy
FQ resistant FQ susceptible
80% P < 0.01

70%
60%
50%
40%
30%
20%
10%
0%
FQ susceptibility infectious complications
(Prostatitis, Sepsis, Epididymitis)
Steensels D. et al., 2011

Blood Prostate Barrier
Perletti and Magri, 2016

Fosfomycin vs. Fluroquinolone in transrectal prostate biopsy
Roberts MJ et al., World J Urol. 2018; 36:323-330. 31

Faecal E. coli before/ after SD prophylaxis 500mg
Ciprofloxacin (n=91) growing on FQ selective agar
PFGE
% E. coli Ciprofloxacin resistant
P = 0.05
Wagenlehner F. et al. Int J Antimicrob Agents, 2000

targeted vs. empiric prophylaxis
(open study in 457 men)
80%
3%
70% 2,6%
3%
60% P=0.12
50% 2%
40%
2%
30%
1%
20%
10% 1%
0% 0,0%
0%
symptomatic UTI
rectal swab + rectal swab -
targeted prophylaxis empiric prophylaxis
NNT – 38 men
Taylor AK et al. J Urol 2012
Rectal preparation with povidone-iodine
6 studies
p=0.0001
Pilatz A et al., EAU 2018

JLU GIESSEN
Sepsis after transperineal prostate biopsy
Grummet JP, et al. BJUint 2014

Strategies minimizing infectious
complications
• Indication for prostate biopsy
– Control elevated PSA
– Prostate MRI
• Selecting for risk factors
– Risk of fluoroquinolone resistant pathogens
• Fluoroquinolones last 6 – 12 months
• Travel history in countries with high prevalence
– Diabetes mellitus, prostate size
• Alternative antibiotics
Wagenlehner F. et al. Nature Rev. Urol 2014
Antibiotic prophylaxis in 52.349
Patients with radical Cystectomy
Krasnow RE et al., J Urol 2017

Antibiotic prophylaxis in 52.349
Patients with radical Cystectomy
Krasnow RE et al., J Urol 2017

Acute, chronic bacterial prostatitis, CPPS
Shoskes
Male Recurrent UTI
• 42 year old male, 4 UTI’s in past year

• 2 culture proven E. coli, resistant to quinolones
• First treated with nitrofurantoin for 10 days and rapidly
recurred
• Rest treated with 2 weeks of Bactrim. Resolved but recurred
3-6 weeks later
• All afebrile
• Prostate exam 25g, nontender
• Post void residual 20 cc
NIH Classification of Prostatitis
• Category I
– Acute Bacterial Prostatitis
• Category II
– Chronic Bacterial Prostatitis
• Category III
– Chronic Pelvic Pain Syndrome
• Category IV
– Asymptomatic Inflammation
Category II:Chronic Bacterial Prostatitis
• Definition has evolved based on minimal data (Urology 2005 Jul;66:2)
– all chronic prostatitis is bacterial (1930)
– four glass test to prove prostatic source for bladder infection (1968)
– significant bacteria recovered from prostatic fluid in absence of UTI (1978)
– NIH category II: syndrome of recurrent UTI with same bacteria that can be
recovered from prostate in between UTI
• JAMA. 1999 Jul 21;282(3):236

Which Bacteria?
• Gram negative, Enterococcus?

– Yes
• Staph (epi, aureus, sapro), Strep?
– first presentation -> probably
– heavily pretreated -> probably not
• Mycoplasma, ureaplasma, chlamydia
– clear in urethritis, CBP pathogen unclear, category II probably not
Patient Evaluation
• A complete history and physical
• urinalysis, urine culture
• EPS and/or VB3 culture off antibiotics for at least 2 weeks(no

WBC evidence)
– pre and post massage urine clinically equivalent to 4 glass test ;
semen is not
• Nickel JC, Shoskes DA, et al. J Urol 176:119, 2006
• Ultrasound post void residual

Antibiotic Selection
• Adequate spectrum for typical bacteria

• Adequate prostate penetration
– lipid soluble, high pKa, low serum protein binding
• Int J Antimicrob Agents. 2005 Jul;26(1):1-7
• Best candidates
– quinolones, sulphas, macrolides, tetracyclines
– fosfomycin (oral q3 days) re-emerging as potential therapy,
especially in multi-drug resistant Gram negatives
• Los-Arcos et al, Antimicrob Agents Chemother 14:1854, 2015

Course of Therapy
• 4-6 weeks of therapy typical
• Warn patients of complications

– diarrhea
– photosensitivity
– tendon rupture with quinolones
– esophagitis with tetracyclines
Results with Antibiotic Therapy
• Difficult to compare studies

– variable agents, treatment duration, follow-up,
endpoints (culture vs clinical)
• Bacteriologic cure
– TMP-SMX median 38%
– ciprofloxacin 60-86%
– lomefloxacin 63%
• Naber, in Nickel (ed) Textbook of Prostatitis 1999
• Wagenlehner et al, In J Antimicrob Agents, 2005
Options for Treatment Failure
• If bacteria gone but symptoms unchanged, treat as category III

(CP/CPPS)
• Long term low dose suppressive therapy
• TURP for large prostatic calculi contained within surgical capsule
• In extreme cases without stones or stones outside surgical
capsule and severe multidrug resistant infections can consider
total prostatectomy
• Other therapies to disrupt biofilm or improve penetration (minimal
data)
– low intensity lithotripsy, direct injection, recurrent prostatic massage
CP/CPPS: Current Standard of Care
• Diagnosis based on pain between the nipples
and knees of a middle aged man +/- LUTS
supplemented by “boggy prostate” and
“classic cystoscopic appearance of
prostatitis”
• Urinalysis and possibly a urine culture
• Prolonged antibiotics courses possibly
supplemented by alpha blockers, NSAID’s,
PPS, finasteride
• Finally, referred to pain management or
psychiatry
• One year treated improvement 17%
Practical Guide to UPOINT
http://www.upointmd.com
• After you make a diagnosis of CPPS
– CPSI to assess symptom severity (NOT
diagnosis)
– Ask about depression and catastrophizing
– Ask if pain relieved by voiding
– Ask if pain outside pelvis or other syndromes
– Palpate pelvic musculature during DRE and
assess for muscle spasm and trigger points (this
is EASY to do and NOT SUBTLE!!!)
– Culture urine including mycoplasma/ureaplasma
and culture EPS or post massage urine
– Check a post void residual by ultrasound
Urinary
• Diagnose
– Bothersome urinary symptoms
– CPSI urinary score > 4
– PVR > 100 cc
• Treat
– Alpha blockers, Anti-muscarinics, beta 3 agonists
– Dietary changes (eg. caffeine, spicy foods)
– Consider neuromodulation for failures
Psychosocial
• Diagnose
– Clinical depression
– Helplessness and hopelessness about condition (catastrophizing)
• Treat
– Appropriate referral
– Anti-depressants
– Stress reduction
– Cognitive behavioral therapy
Organ Specific
• Prostate • Bladder
– Diagnose – Diagnose
• pain improved by
voiding
• tenderness
• positive lidocaine
• WBC in EPS
infusion test
• hematospermia
– Treat
• quercetin (eg. Cysta-Q)
– Treat
• PPS (I no longer use)
• quercetin
• dietary changes
• bee/rye pollen
• Cyclosporine
• cernilton
eg. Prosta-Q, Q-Urol
Infection
• If current or recurrent UTI, then positive

culture = chronic bacterial prostatitis
• CPPS patients may have episodes of
urethritis (ureaplasma) or uropathogenic
bacteria in EPS without UTI of unclear
significance
• In these specific circumstances antibiotics
are indicated
• Special case: cultures always negative but
always resolved with antibiotics
Neurologic/Systemic
• Diagnose
– pain outside the lower abdomen, genitals, pelvis
– fibromyalgia
– chronic fatigue syndrome
– irritable bowel syndrome
• Therapy
– tricyclic antidepressants (eg Elavil)
– gabapentin, pregabalin
Tenderness of Skeletal Muscles
• Diagnose
– spasm and/or trigger points of pelvic and/or
abdominal muscles
• Treat
– pelvic physical therapy (eg myofascial release)
– trigger point injection
– stress reduction
– muscle relaxants
– low intensity shock wave lithotripsy
Prospective Study of UPOINT Directed
Multimodal Therapy
• 100 patients, followed minimum of 6 months

(average 50 weeks)
• Offered at least one therapy for each positive
domain
• Excluded if never re-examined or if refused to
do any of the therapies (but did not have to
agree to all)
• Powered to 90% to detect a 1.2 point drop in
total CPSI
• Shoskes et al, Urology 75:1249, June 2010
Results
• similar incidence of phenotypes to prior study
• 84 patients improved by primary endpoint (at
least 6 point drop in total CPSI score)
• 50 patients achieved at least 50% drop in
total CPSI score
• # of domains or therapy did not significantly
alter chance of improvement
• only therapy that affected drop in score
independently was quercetin (multiple
mechanisms?)
Summary
• The UPOINT system provides a simple and

valid way to phenotype CPPS patients in a
clinically relevant way
• Multimodal therapy based upon the UPOINT

phenotype has a high chance of patient
improvement (part of Canadian Urological
Association Guidelines)
• UPOINT can provide the framework to

integrate future biomarkers and therapies
Complicated UTI, Urosepsis
Wagenlehner
ORENUC Classification of risk factors
Bjerklund-Johansen T.E. et al. 2011 International J Antimicrobial Agents

Complicated UTI
Flores-Mireles 2015
Urology Giessen - Collected Isolates: n=1025
Next Generation Sequencing
Enterococcus faecium, 25
E.coli, 426
Enterococcus faecalis, 289
Pseudomonas aeruginosa,
41
Proteus vulgaris, 12
Proteus
Proteus sp., 28 mirabilis,
50 Citrobacter freundii, 2
Citrobacter koseri, 7
Klebsiella sp., 23
Klebsiella Enterobacter Enterobacter aerogenes, 8
Klebsiella pneumoniae, 59 oxytoca, 30 cloacae, 25
Fritzenwanker et al. Clin Microbiol Infect 2016

Case vignette
• 72-year-old woman with a history of hypertension and urgency urinary incontinence
presents to the emergency department with a 1-day history of acute-onset abdominal pain
in the left lower quadrant.
• Before the onset of abdominal pain, she had had constipation for 3 days and had not
urinated for 1 day despite her efforts to drink plenty of water.
• Extended-release oxybutynin (30 mg daily)
• Temperature 36.7°C, blood pressure 126/75 mm Hg, heart rate 100 beats per minute,
respiratory rate 18 breaths per minute, oxygen saturation 99%
• On examination tenderness to palpation of the left lower quadrant of the abdomen.
• Alert and fully oriented.
• Cardiac and pulmonary examinations normal.
• Creatinine 2.0 mg/ dl (180 μmol per liter), anion gap 21 mmol/ l, white-cell count 24,200/
per cubic millimeter (predominant neutrophils), hematocrit 45.0%, lactate 3.9 mmol/ l
• CT abdomen shows large stool volume in the descending and sigmoid colon without
evidence of gastrointestinal wall edema or hypoenhancement.
• A chest radiograph shows clear lungs without focal consolidations.
• An indwelling urinary catheter is placed, and 1 liter of urine is drained.
• Urinalysis shows leucocytes
Michael Y Mi, NEJM 2019

Asymptomatic bacteriuria in different
cohorts – Metaanalysis
Köves B et al. Eur Urol 2017

Asymptomatic bacteriuria in pregnancy-
Metaanalysis
Köves B et al. Eur Urol 2017

Case vignette
• 37 years man
• Early childhood brain damage, tetraplegic
• Bilateral Ureteral stenoses
• Bilateral DJ-stents
• Suprapubic bladder catheter
• Bilateral stagghorn calculus
• 24 breath/ min
• Blood pressure 95/ 65 mm Hg
• Somnolent
New Sepsis Definitions
quick SOFA criteria
• Respiratory rate ≥ 22/ min

• Altered mentation
• Systolic blood pressure ≤ 100 mmHg
Singer M et al., JAMA 2016

New Sepsis Definitions
Singer M et al., JAMA 2016

Risk factors for specific pathogens
Pathogen OR
UTI in past 12 months Klebsiella spp. 1.9
Hospitalisation in past 6 months Klebsiella spp. 2.5

Pseudomonas spp. 1.8
Antibiotic therapy in past 3 months Candida spp. 2.6
Klebsiella spp. 1.8
Urinary stones Pseudomonas spp. 2.4
Urinary catheter (all forms) Pseudomonas spp. 2.7

Suprapubic catheter Proteus spp. 2.4
Ureter catheter Candida spp. 3.2
> 3 risk factors Candida spp. 2.8
Klebsiella spp. 2.2
Pseudomonas spp. 2.0
Bjerklund-Johansen T.E. et al. Int J Antimicrob Agents 2006
Ceftolozane/ Tazobactam susceptible
Case vignette
• 65 years patient
• On dialysis
• Found unconsciosus at home (GGS 6)
• Blood pressure 80/40 mm Hg
• 25 breaths/ min
• No urine output
• Noradrenaline 30 µg/ml
Case vignette
• Leucozytes 34,7 giga/l
• Procalcitonin 12,4 µg/l
• Lactate 7,5 mMol/l
• Cholinesterase 1790 U/l
• Platelets 80 x10³/ml
• pH: 7,30
Serum Lactate and mortality in sepsis
Mikkelsen M et al. Crit Care Med 2009;37

25
Recommended antibiotic therapy
for urosepsis
Imipenem + Clindamycin
PAMPs Alarmins
exogenous endogenous
(e.g. LPS) (e.g. mitochondrial DNA)
DAMPs
exogenous + endogenous
PRRs
(e.g. TLRs)
Inflammatory response
PAMP-pathogen associated molecular pattern; HMGB1-high mobility group box 1; DAMP-damage
associated molecular pattern; PRR-pattern recognition receptor; TLR-toll like receptor
Sarhan M et al., Cell death and disease 2018
Sensitive E. coli in aspirates
Lactate clearance
Lactate as marker of success
Mortality
Lactate clearance
100% Cut-off 32,8%/ 12h
90%
P<0,0001
80%
70%
60%
50%
40%
30%
20%
10%
0%
Laktat > 10mmol/l (>24h) Laktat > 10mmol/l (<24h)
Haas S. et al., Intensive Care Med 2015

26
Case vignette
• Drainage of renal abscess, aszites
• E. coli multi sensitive
• Initial Imipenem + Clindamycin
• Noradrenaline ceased
• Continuously elevated CRP
• Secondary nephrectomy
Sexually transmitted infections
Shoskes
CDC Guidelines
• “one stop” internet site

– http://www.cdc.gov/STD/
STD/STI
• 28 year old male presents to urology clinic with “penile pain”

• After refusing to answer questions by your medical assistant,
nurse or resident, it turns out he went to a strip club and
unbeknownst to his wife received oral sex while wearing a
condom
• Since he has penile pain and burning with urination
• Has seen 2 Urologists, a GP and 2 infectious disease doctors
• All tests negative and multiple courses of antibiotics have not
helped
STDs by Presentation
• Male urethritis
• Male genital ulcers

Male Urethritis
• Symptoms: dysuria, itch, discharge
• Most common organisms:

– NG
– Chlamydia
– Others
(Mycoplasma, Ureaplasma, Gardnerella)
Male Urethritis Diagnosis
• Urine nucleic acid test for NG and Chlamydia
• Urethral swab
– Seldom used but source of exam questions
– Gram stain
• Intracellular G-neg diplococci = gonorrhea
• WBC no bacteria: non-gonococcal urethritis
– Culture in Thayer-Martin medium

• Inhibits growth of other microbes
• Allows growth of Neisseria

Male Urethritis: Simplest Treatments
• Uncomplicated gonorrhea
– Ceftriaxone 125 mg IM or cefixime mg 400 po,
also azithromycin 1g (30% have Chlamydia)

– No quinolones! Too much resistance
• Nongonococcal urethritis
– Goal: cover Chlamydia and Ureaplasma
– Azithromycin lg single dose

Male Urethritis: Partner Treatments
• Longstanding recommendation: evaluate and treat all
partners exposed within 60 days; if none, evaluate and
treat the most recent partner
• New idea: expedited partner therapy
– Give patient Rx or meds, to take to partner
– Advantage: partner more likely to be treated
– Some states don’t allow this
– CDC web site

http://www.cdc.gov/std/ept/legal/default.htm
Genital Ulcers
• STDs
• Remember: not all ulcers are STDs! Can also
be:
– Carcinoma
– Erythema multiforme
– Fixed drug eruption
– Bechet’s disease
– Lichen planus
STDs With Genital Ulcers
• Uncommon in USA
– Granuloma inguinale
– Lymphogranuloma venereum
• Common in USA
– Painless: 1o syphilis (unless superinfected)
– Painful
• Chancroid
• Herpes
Ulcer STDs Common in USA
• Painful
– Herpes simplex
– Chancroid
• Syphilis is usually painless unless superinfected

Genital Herpes: Diagnosis
A group of vesicles on erythematous base that does not
follow a neural distribution: pathognomonic*
Other tests:
– Virus culture of lesions
– PCR more sensitive but not FDA-approved
– Point of care blood tests are good but 2 caveats
• Negative early (before antibodies form)
• Positive for life (current vs past infection?)
Genital Herpes: Treatment
• Acyclovir po (topical not effective)
• Newer drugs with better oral bioavailability

– Valacyclovier (valine ester of acyclovir)
– Famciclovir
• The same drugs can also be used for recurrences

– PRN dosing
– Chronic suppression
• Counsel patient (see next slide)

Genital Herpes: Patient Counseling
Expect recurrences
Possible transmission to baby during delivery
Ways to decrease risk of transmission to partners
– Abstain during symptoms (problem: may shed
virus even if not having symptoms)
– Condoms
– Valacyclovir 500 mg daily taken by patient

Chancroid (Haemophilus ducreyi)
Symptoms
– One or more painful ulcers
– 1/3 have tender or suppurative nodes
Diagnosis
– Specialized culture is not widely available
– PCR test available but not FDA-approved
– OK to treat painful ulcer if not herpes or syphilis
Simplest treatment
– Azithromycin lg po single dose
– Treat partners
Syphilis (Treponema pallidum)
1o stage is painless ulcer
STDs with Ulcers:
Sorted by Appearance
• Painful vesicles: herpes
• Bubos, ulcer small or absent:
lymphogranuloma venereum:
• Typical raw ulcer
– 1o syphilis
– Chancroid
– Granuloma inguinale
Syphilis (Treponema pallidum)
Stages and Symptoms
1o: painless ulcer (chancre)
2o: nongenital skin lesions, adenopathy
3o: cardiac, neuro, eye, ear, etc.
Latent: no symptoms
Syphilis Diagnosis
• Scrape base of ulcer, look for spirochetes by dark-field
microscope or fluorescent antibody
– Best test for primary syphilis
– Many docs lack equipment
• Serum antibody tests

– Nontreponemal (anti-cardiolipin antibodies)
– Treponemal (antibodies against Treponema)

Diagnosis of Syphilis
• Recent change in recommendations due to high
false positive with non-treponemal test
• now recommend starting with treponemal assay

(syphilis IgG) and if reactive confirm with RPR
• If IgG positive and RPR negative use second

treponemal assay (TPPA or FTA antibody) to
confirm and differentiate latent vs historical
Treatment of 1 and 2° Syphilis
Benzathine penicillin G 2.4 million units IM
– Bicillin L-A (benzathine PCN)
– Not Bicillin C-R (benzathine- procaine PCN)
If allergic to penicillin, can use tetracycline or

doxycycline 2 weeks, but only if:
– Not pregnant
– Reliable for follow-up

“Spousal Revenge Syndrome”
• Described cohort of 8 men, developed symptoms of
STD/pelvic pain after sexual encounter outside of marriage
(often protected)
• All cultures and STD tests negative
• Antibiotics gave temporary or no improvement
• Our eval all cultures negative, all had pelvic floor spasm
• If treated spasm, symptoms improved but many refused
– Makovey et al, Can J Urol 21:8176, Feb 2016

Novel antibiotics in UTI
Naber
A. There are still „old“ antibiotics
which can be used for treatment of
uncomplicated UTI
• Fosfomycin
• Nitrofurantoin
• Pivmecillinam
• Nitroxoline
B. „Novel“ antibiotics for complicated UTI
Analogues of known antibiotic classes
 Cephalosporins + BLI:
i) new cephalosporin (Ceftolozane) with an „old“ BLI (tazobactam)
(registered)
ii) an old cephalosporin (ceftazidime) with a „new“ BLI (Avibactam)
(registered)
 Carbapenems (old) + BLI (new)

 i) Imipenem + Relebactam (ph3)
 ii) Meropenem + Vaborbactam (Carbavance) (registered)
 Siderophore cephalosporine (Cefiderocol) (ph3)
 Aminoglycosides, e.g. Plazomicin (ph3)
Grundstruktur der Penicilline (oben) und Cephalosporine
(unten). Der β-Lactamring ist rot markiert.
Classification of β‐Lactamases
Bush K, Annals of the New York Academy of Sciences 2013

Ceftolozane/tazobactam
Ceftolozane Tazobactam
• Extended-spectrum novel • β-lactamase inhibitor with high
cephalosporin with activity against binding affinity for Class A (ESBLs)
Enterobacteriaceae and P. aeruginosa1 and some Class C β-lactamases
• Binds penicillin binding proteins,
rapidly bactericidal
Zhanel GG et al. Drugs. 2014;74:31–51.

Activity of Tazobactam against β‐Lactamases

Randomised, controlled phase 3 trial
(ASPECT-cUTI)
Ceftolozane/tazobactam 1.5g tid

versus levofloxacin 750mg qd
in the treatment of patients with cUTI, or

pyelonephritis
Primary and Secondary Efficacy Analysis at TOC
Ceftolozane/ Percentage
NI margin Levofloxacin
tazobactam difference
Composite cure n/N (%)
95% CI n/N (%) (95% CI)
Primary end point
mMITT population 306/398 (76.9) 275/402 (68.4) 8.5 (2.3 to 14.6)
PP population 284/341 (83.3) 266/353 (75.4) 8.0 (2.0 to 14.0)
Microbiological -10 -5 0 5 10 15 20
eradication n/N (%) n/N (%) (95% CI)
PP population 294/341 (86.2) 274/353 (77.6) 8.6 (2.9 to 14.3)
-10 -5 0 5 10 15 20
Clinical cure n/N (%) n/N (%) (95% CI)
mMITT population 366/398 (92.0) 356/402 (88.6) 3.4 (-0.7 to 7.6)
PP population 327/341 (95.9) 329/353 (93.2) 2.7 (-0.8 to 6.2)
-10 -5 0 5 10 15 20
Ceftolozane/tazobactam – levofloxacin Wagenlehner F, et al. Lancet 2015
(difference [%])
Chemical structure of the
novel non-beta-lactam
beta-lactamase inhibitors
avibactam, relebactam and
vaborbactam
Avibactam plus Ceftazidime
Relebactam plus
Imipenem/Cilastatin
Vaborbactam plus Doripenem
Perletti et al 2018
Archivio Italiano di Urologia e Andrologia 2018; 90(2):85-96
Ceftazidime / Avibactam
Ceftazidime Avibactam
• Extended-spectrum cephalosporin • Novel non-β-lactam β-lactamase
with activity against inhibitor with a unique mode
Enterobacteriaceae and of action2
P. aeruginosa1 • High binding affinity for Class A, C
• Binds penicillin binding proteins, and some Class D β-lactamases
leading to bacterial cell lysis1 (ESBLs, KPCs and AmpC), some
of which (e.g. KPCs) are unaffected
by current BLIs3
1. Hayes MV, Orr DC. J Antimicrob Chemother. 1983;12:119–126; 2. Ehmann DE et al. Proc Natl Acad Sci. 2012;29:11663–11668; 3. Aktaş Z et al. Int J Antimicrob
Agents. 2012;39:86–89; 4. Kimura S et al. Antimicrob Agents Chemother. 2004;48:1454–1460; 5. Crandon JL et al. Antimicrob Agents Chemother. 2012;56:6137.
Activity of Avibactam against β‐Lactamases

A Phase 3, Randomized, Multicenter, Double-Blind,
Double-Dummy, Parallel-Group, Comparative Study to
Determine the Efficacy, Safety, and Tolerability of
Ceftazidime Avibactam 2.5g tid vs Doripenem 500mg tid
followed by Appropriate Oral Therapy in the Treatment of cUTI

or Acute Pyelonephritis, With a Gram-Negative Pathogen in
Hospitalized Adults (RECAPTURE 1 and 2)
Primary and Secondary Efficacy Analysis at TOC
Ceftazidime/ Percentage
NI margin Doripenem
avibactam difference
Composite cure n/N (%)
95% CI n/N (%) (95% CI)
Primary end point
Microbiological -10 -5 0 5 10 15 20
eradication n/N (%) n/N (%) (95% CI)
-10 -5 0 5 10 15 20
Clinical cure n/N (%) n/N (%) (95% CI)
mMITT population 332/393 (84.5) 360/417 (86.3) -1.9 (-6.8 to 3.0)
-10 -5 0 5 10 15 20
Ceftazidime/avibactam – Doripenem
(difference [%]) Wagenlehner F et al. Clin Inf Dis 2016
Phase 2
Treatment of complicated UTI/pyelonephritis (n=298)
Imipenem/cilastatin+relebactam 250 mg, vs.

Imipenem/cilastatin+relebactam 125 mg vs.
Imipenem/cilastatin 500 mg every 6 hours
Imipenem/relebactam Imipenem/relebactam Imipenem

250mg 125mg 500mg
Microbiological 95.5% 98.6% 98.7%

response at EOT
Clinical 97.1% 98.7% 98.8%
response at EOT
Safety: Both relebactam-containing regimens were well tolerated

Sims L et al., JAC 2017
Clinical development of meropenem-
vaborbactam (Carbavance)
Two Phase III trials
– TANGO 1 (NCT02166476)
Efficacy, safety, and tolerability of meropenem-
vaborbactam vs piperacillin-tazobactam for cUTI,
including acute pyelonephritis
– TANGO 2 (NCT02168946) – stopped early

Efficacy, safety and tolerability of meropenem-
vaborbactam vs best available therapy in serious
infections (cUTI or AP, cIAI, HAP, VAP, and/or
bacteraemia) due to carbapenem-resistant
Enterobacteriaceae
https://clinicaltrials.gov/
Phase 3
Meropenem + vaborbactam vs. BAT in infections with
carbapenem resistant Enterobacteriaceae
(n=72 / 43 microbiologically evaluable CRE)
Meropenem/ BAT p
vaborbactam
Clinical Cure 64.3% 33.3% P = 0.04
at EOT
Clinical Cure 57.1% 26.7% P = 0.04
at TOC
http://www.themedicinescompany.com/investors/news/medicines-company-present-new-data-tango-ii-study-vabomere%E2%84%A2-meropenem-and-vaborbactam 2017
Bacterial Resistance Mechanisms
https://www.google.de/search?q=bacterial+resistance+mechanisms&tbm=isch&tbo=u&source=univ&sa=X&ved=0ahUKEwj1tbW
DpNjZAhUNmbQKHTWoC6UQ7AkIeg&biw=1813&bih=731&dpr=0.75#imgrc=xAEtNinCV3eWgM:&spf=1520359429062
S-649266 – Cefiderocol
Siderophore Cephem
• Iron-regulated outer membrane proteins (IROMP) are induced
under iron deficient conditions
• S-649266 is actively transported via IROMP under iron deficient
conditions
• S-649266 is highly stable against ESBL and carbapenemase
enzymes, including KPCs and metallo-beta-lactamases
Ito et al 2016 AAC

Mechanism of Action of S-649266 Cefiderocol
 Iron-regulated outer membrane proteins (IROMP) are induced under iron deficient
conditions
 S-649266 is actively transported via (IROMP) under iron deficient conditions
 Potent in vitro activity of S-649266 under iron-deficient conditions was observed when
Mueller-Hinton Broth is supplemented with apotransferrin
Other b-lactams:
Fe3+ Passive transport
Cephem Carbapenem
Compound Y S-649266
IROMP Fe3+ Active transport
cirA and fiu in E. coli
piuA in P. aeruginosa
Porin
Outer
membrane
Fe3+
Fe3+ PBP PBP PBP
Periplasm
Inner
membrane
PBP: Penicillin binding protein
Fe3+
117
A Phase 2, Multicenter, Double-blind,
Randomized, Clinical Study to Assess the
Efficacy and Safety of
IV S-649266 2g (Cefiderocol) tid vs IV

Imipenem/Cilastatin 1g tid
in cUTI or Pyelonephritis Caused by Gram-

Negative Pathogens in Hospitalized Adults
(APEKs-cUTI)
Phase 3 APEKS-cUTI Trial in Patients with cUTI:
Cefiderocol 2g t.i.d. vs. Imipenem/Cilastatin 1g t.i.d.
Composite Cure
Cefiderocol Imipenem % Diff

n/N (%) n/N (%) (95% CI)
Combined Cure at TOC 183/252 (72.6) 65/119 (54.6) 18.58 (8.23,

(app. 7 days after EOT) 28.92)
Shinogi 2017; http://www.shionogi.com/newsroom/article.html#122507

Plazomicin*
AAC 2010;54:4636-42
*evades aminoglycoside-modifying enzymes;

active against most KPC-producing pathogens
Munoz-Price LS et al. Lancet Infect Dis. 2013;13:785–796
A Phase 3, Randomized, Multi-Center,
Double-Blind Study to Evaluate the
Efficacy and Safety of
Plazomicin 15mg/kg qd
versus Meropenem 1g tid
followed by Optional Appropriate

Oral Therapy for the Treatment of
cUTI or acute pyelonephritis
Plazomicin 15mg/kg vs Meropenem 1g in complicated UTI (EPIC Study)
Composite Cure at the Test-of-Cure Visit, according to Patient Subgroups in the Microbiologic Modified Intention-to-Treat
Wagenlehner F et al., N Engl J Med 2019; 380:729-40

Conclusions
• Penicillin/betalactamase inhibitor (BLI)
- effective strategy in the past, e.g. piperacillin/tazobactam
• Novel combinations with cephalosporins/BLI

- enlarged antibacterial spectrum, incl. ESBLs/Carbapenemases
• Novel combinations with carbapenems/BLI

-enlarged antibacterial spectrum, incl. ESBLs/Carbapenemases
• Novel siderophore cephalosporine

- resistant to different resistance mechanisms
• Novel aminoglycoside
- active in XDR pathogens
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Uro-Genital Tract Infections: Emerging Threats and

Saturday, May 4, 2019

Infections of the urogenital tract

Ingested bacterium Ingested bacterium

Die Zeit 2015

Human Microbiome Project, Nature 2012 2

Uncomplicated UTI Pyelonephritis Complicated UTI

Low risk High risk

Bonkat G et al. 2018 EAU guidelines infection

International Consultation on Urogenital Infections, EAU 2010

O‘Neill Report on Antibiotic Resistance

Cek M et al., WJU 2014

Cek M et al., WJU 2014

Schwaber, Carmeli 2011 JAC

Distribution of countries in which NDM-1-producing Enterobacteriaceae

Jean & Hseuh. Int J Antimicrob Agents. 2011;37:291-5

Baron et al 2016 IJAA

IDSA Public Policy. Clin Infect Dis. 2011;52(Suppl 5):S397-S428.

Center for Disease Dynamics, Economics & Policy. 2015.

Mod. after Johnson JR, Russo TA, NEJM 2018

Hooton T et al., NEJM 2013; 369: 1883-1891

Mod. after Johnson JR, Russo TA, NEJM 2018

Armand-Levefre et al. 2018

Armand-Levefre et al. 2018

Bonkat G et al. EAU guidelines 2019

Huttner A et al., JAMA. 2018; 319:1781-1789

Total antibiotic prescriptions

Gagyor I. et al., BMJ 2015;351:h6544

Wagenlehner F et al. Urol Int. 2018; 101:327-336

Study Pyelonephritis (n)

Wagenlehner et al. (2018) CanUTI-7 5 [1,5%](BNO 1045),

Johnson JR, Russo TA, NEJM 2018

Bonkat et al. 2019 EAU guidelines

Johnson JR, Russo TA, NEJM 2018

Bonkat et al. 2019 EAU guidelines

• Within 3 – 4 months of an initial UTI, 20-30%

Treatment of acute cystitis is not enough !!!!

Foxman, Am J Med, 2002, 113, 3, 5S-13S

Behavioural General Urogenital

49-year old female patient

Tenke P. Urological infections 2011 InTech

 Fluid intake – around 2 liters/day

Bonkat et al. European Association of Urology Guidelines on Urological Infections 2018

days with intercourse days diaphragm and spermicide used

Hooton et al (1996) N Engl J Med 335:468-474

RRP= 0+0+40 +0+40 +50=130≈ 0.6

Cai et al., 2014

• Daily/weekly reduced doses of antimicrobials

*In women with >3 episodes per year

Grabe M, et al. EAU Guidelines on Urological Infections 2014 www.uroweb.org

Daily or after intercourse

Bonkat et al. EAU Guidelines on Urological Infections 2018 www.uroweb.org

Dethelfsen et al. PLoS Biol. 2008;6(11):e280

Placebo (n=43) Estriol (n=50)

• Probiotics containing strains L. rhamnosus GR-1, L. reuteri

Stapleton et al 2011 CID 52:1212

Cochrane review 2012:

Jepson RG et al. Cranberries for preventing urinary tract infections (Review) .

Kranjcec et al 2014 World J. Urol. 32:79-84

Mean number of episodes of

urinary tract infections

Bonkat et al. European Association of Urology Guidelines on Urological Infections 2018