Complicated Urinary Tract
Infection Syndromes
Robert A. Bonomo, MD
Infectious Diseases
Case Western Reserve University School of Medicine
Copyright: ROBERT A. BONOMO, M. D 2014
Appreciation
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CIDEIM
ASM
Dr. Maria Virginia Villegas
Dr. Cesar Arias
Sponsors of the Satellite
Symposium, Merck Sharpe and
Dohme
• NIH, VA
Copyright: ROBERT A. BONOMO, M. D 2014
Outline
• Basic definitions
• Challenges
– ASB in Pregnancy *
– Pyelonephritis
– Surgical pt and CAUTI
– Elderly
– Diabetes
– Spinal Cord Injury
– Renal transplant
• Comment on MDR UTIs
Copyright: ROBERT A. BONOMO, M. D 2014
UTIs
• Most common primary care dx for women
• Community: In 2007 in the US there were 10.5
Million ambulatory visits for UTI (0.9 % of all
ambulatory visits); 21.3%) of these visits were
to hospital EDs.
• Hospital: Prevalence is high in the hospital
– in a 2004 survey of symptomatic UTI among 49
Swiss hospitals, UTI was detected in 3.7% of those
who had been catheterized for at least 24 hours
during their hospital stay, and in 0.9% of those who
had not been catheterized (4x)
Copyright: ROBERT A. BONOMO, M. D 2014
Risk Factors for UTI
• Female sex
• Prior UTI
• Trauma/manipulation
– Sexual activity
– Condom/diaphragm/spermicide use
– Catheter
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Vaginal infection
Diabetes
Obesity
Genetic susceptibility/anatomic abnormalities
Copyright: ROBERT A. BONOMO, M. D 2014
Disease Burden
• Women with UTI average 3.83 symptom
days and 2.89 restricted-activity days
• Risk of cystitis progressing to pyelonephritis
is about 1%
• Urinary tract is the most common source of
E coli bacteremia
Copyright: ROBERT A. BONOMO, M. D 2014
UTI Recurrence
Significant disease recurrence rate;
bacterial persistence?
Copyright: ROBERT A. BONOMO, M. D 2014
Host Factors
Host response
Bacterial Factors
Manipulation
Catheter Insertion
Sexual activity
Susceptible
Urination
Host response
ASB
UTI/Pyelo
Host response
Bacterial adaptation
There also exists polymorphisms in genes coding for inflammatory response (TLRs,
interferon regulatory factors, and chemokine receptors) between individuals with ASB
and pyelonephritis
Copyright: ROBERT A. BONOMO, M. D 2014
Copyright: ROBERT A. BONOMO, M. D 2014
Uropathogenic E. coli use P fimbriae to bind to UT epithelial cells
and colonize the bladder.
These adhesins bind D-galactose-D-galactose groups on the
P blood group antigen of rbcs and uroepithelial cells cells
Copyright: ROBERT A. BONOMO, M. D 2014
P fimbriae : Pyelonephritis associated pili
“D galactose groups”
1% of the population lacks this receptor, and its presence or
absence dictates an individual's susceptibility
or non-susceptibility, respectively, to E. coli UTIs.
Copyright: ROBERT A. BONOMO, M. D 2014
During the course
of a urinary
tract infection,
many of the
bacteria become
transiently
filamentous
in response to
innate host
defense
mechanisms
Uropathogenic E. Coli (UPEC)
SEM image of uropathogenic E. coli (UPEC) bound to,
and emerging from within, mouse superficial epithelial cells
that line the lumenal surface of the bladder
Copyright: ROBERT A. BONOMO, M. D 2014
Etiology of recurrent UTIs
Copyright: ROBERT A. BONOMO, M. D 2014
Bacteriology-I
• The bladder is continuously
invaded by bacteria
(substantial numbers before
spontaneous clearance!)
• E. coli causes the majority of
syndromes
Copyright: ROBERT A. BONOMO, M. D 2014
Bacteriology-II
• E coli 74.4% among outpatients regardless of
age group; 65% of hospital acquired infections,
and 47% of health care–associated infections.
• Uropathogenic strains; ESBL producers (ST131)
• Non E. coli (resistance)
– Klebsiella spp, Pseudomonas aeruginosa, and
Proteus spp,
– Streptococcus agalactiae and Staphylococcus
saprophyticus.
– MRSA in SCI patients
Copyright: ROBERT A. BONOMO, M. D 2014
Bacteriology-III
• Treatment of UTIs from MDR organisms is
complicated by limited PO options and
may require a return to older antibiotics,
combination therapy, or IV agents.
Copyright: ROBERT A. BONOMO, M. D 2014
Major Complicated UTI Syndromes
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ASB in Pregnancy *
Pyelonephritis,
CAUTI
Elderly
Diabetes
Spinal Cord Injury
Renal transplant
MDR UTI
Copyright: ROBERT A. BONOMO, M. D 2014
ASB, Asymptomatic Bacteriuria
• + Culture, + UA
• The urinary tract -a portal to the outside, and
susceptible to invasion by microbes.
• Among men, culture of a random initial void will
find 1% to 5% colonized with Escherichia coli;
• The overall prevalence of ASB in women is 3.5%,
but is much higher following sexual intercourse.
• IDSA –in general, don’t screening or rx ASB
• Prevalence of ASB increases with age
Copyright: ROBERT A. BONOMO, M. D 2014
ASB that needs Rx
• Except pregnancy, ASB is not a treatable
condition. Treating ASB leads to complications
• The prevalence of ASB in pregnancy ranges
from 2% to 20%; and one-fifth to two-fifths of
these may develop life threatening
pyelonephritis
• Screening and treating ASB during pregnancy
may reduce this risk by 77%
Copyright: ROBERT A. BONOMO, M. D 2014
Pyelonephritis
• Urinary symptoms may or may not be present in
pyelo;
• Fever and chills, back pain, nausea, and
vomiting.
• Incidence of pyelo is an order of magnitude
lower than cystitis (59.0/10,000 for females and
12.6/10,000 for males), but the patterns by age
and sex are very similar.
• Bacteremia; MDR UTI and rx options
Copyright: ROBERT A. BONOMO, M. D 2014
CAUTI
• Every day that a urinary catheter is in place
increases the risk of bacteriuria by 3% to 10%.
• No sx
• Catheters --major risk factor for HA UTI,
almost 1/3 of all HA infxs.
• Opinion….Catheter type? antimicrobialimpregnated, antiseptic- coated (silver alloy),
and standard polytetrafluoroethylene-coated
catheters-no difference
Copyright: ROBERT A. BONOMO, M. D 2014
CAUTI…by the numbers-I
• Rates of CAUTI vary by service: in an analysis
of 15 hospitals in the Duke Infection Control
Outreach Network, the rates were 1.83 /
1000 catheter days for patients in ICU, vs.
with 1.55/1000 catheter days for other
patients.
Copyright: ROBERT A. BONOMO, M. D 2014
CAUTI…by the numbers-II
• Catheter placement increases risk of UTI by as
much as 4-fold.
• In US, estimates of the point prevalence of
CAUTI (based on the National Nursing Home
Survey and National Home and Hospice Care
Survey) are 5.2% among nursing home
residents, 3.6% among those receiving home
health care, and 3% of those receiving
hospice care.
Copyright: ROBERT A. BONOMO, M. D 2014
CAUTI…by the numbers-III
• Surgical patient…Undergoing surgery increases
UTI risk, especially if it involves manipulation of
the genitourinary tract and placement of a
urinary catheter.
• Overall, UTI incidence (30 days p sx is 1.7%, but
vs 2.6% among patients undergoing
nonalimentary and noncolorectal tract sx vs
5.6% for those undergoing abdominoperineal
resection
Copyright: ROBERT A. BONOMO, M. D 2014
UTI in Elderly
• Risk of UTI increases with age.
• The annual incidence of UTI among very old
women in Sweden (85 y +) was 29.6%.
– vertebral fractures, incontinence, inflammatory
rheumatic disease, and multi-infarct dementia
• In the Leiden 85-Plus Study, the incidence of UTI
among women was 12.8 /100 person-years, and
7.8/ 100 person-years among men.
• Predictors of UTI risk -cognitive impairment,
disability in ADLs, recent hx of UTI, and urinary
incontinence
Copyright: ROBERT A. BONOMO, M. D 2014
Different risk factors by age group
Copyright: ROBERT A. BONOMO, M. D 2014
UTI in DM
• Why?
– Glucosuria, impaired immune or WBC
function
• SGLT2 (serum glucose cotransporter-2)
inhibitors, produce high levels of
glucosuria-small increase in symptomatic
UTIs men and women.
Copyright: ROBERT A. BONOMO, M. D 2014
Copyright: ROBERT A. BONOMO, M. D 2014
Variables associated with sympt UTIs
or ASB in women with Type 2 DM
Risk Factors for Infection
Symptomatic
Asymptomatic
Not diabetes associated
Age
Age
Diabetes associated
Retinopathy
Any long-term
complication
Oral hypoglycemic
or insulin therapy
Heart disease
Diabetes 5 y
Duration of diabetes
Oral hypoglycemic
therapy
UTI, DM and BMI
In Israel, DM increased the
risk of UTI by 23% in males
24% in females.
Obesity was independently
associated with UTI after
adjustment for age, diabetes,
and vitamin D levels:
males w/ BMI of 50 or > were 2.38 x more likely vs. a BMI
of < 25 kg/m2 to have a UTI;
for females the increased risk was 1.25
Copyright: ROBERT A. BONOMO, M. D 2014
UTI in DM
• Neuropathy -impaired bladder sensation, which
obscures some clinical symptoms of lower tract
infection.
• Diabetic women with pyelonephritis are more
likely to have bilateral renal involvement and
bacteremia.
• Bacteremia common
– In a group of elderly Greek patients hospitalized with
pyelonephritis, bacteremia was identified in 30.7%
with and 11% without diabetes
Copyright: ROBERT A. BONOMO, M. D 2014
DM Rx CX
• Longer duration of fever (median 4.5 vs 2.5 days,
P<.001)
• Longer period of hospitalization (median 10 vs 7
days; P<.001)
• Higher mortality (12.5% vs 2.5% P<.01)
• Cipro failure
Copyright: ROBERT A. BONOMO, M. D 2014
CX DM UTIs
• A case series of 65 consecutive patients with
renal or perinephric abscesses reported 28%
of subjects had DM
• 67% of patients presenting with
emphysematous cystitis were diabetic
• 62% presented with emphysematous
pyelonephritis
• DM not identified as a risk factor for cxs of
severe sepsis or septic shock in pts with
urosepsis
Copyright: ROBERT A. BONOMO, M. D 2014
DM--more likely to
present with
complications of
UTI
(abscesses,
emphysematous
cystitis or
pyelonephritis)
Copyright: ROBERT A. BONOMO, M. D 2014
SCI-I
• Impaired bladder emptying associated with a
neurogenic bladder.
• UTI and renal failure were the most common causes
of death.
• A high bladder pressure leads to vesicoureteral reflux
with hydronephrosis, pyelonephritis, and renal
failure.
• Maintaining a low-pressure bladder in patients who
cannot void spontaneously is usually achieved by
intermittent catheterization or, for men,
sphincterotomy and condom catheter drainage.
Copyright: ROBERT A. BONOMO, M. D 2014
SCI-II
• Surgical procedures such as augmentation
cystoplasty, ileal conduits, or other urinary
diversions are also used for selected patients.
• Some patients with high-level cord injury
may require management with a chronic
urethral or suprapubic urinary catheter.
Copyright: ROBERT A. BONOMO, M. D 2014
Approaches to prevention of urinary
infection in SCI
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Maintain low-pressure bladder
Intermittent catheterization
Sphincterotomy/condom
Neobladder
Intermittent catheterization
Education program (bacteriuria only)
Avoid chronic indwelling catheter
Copyright: ROBERT A. BONOMO, M. D 2014
Not effective in SCI
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Antimicrobial prophylaxis
Cranberry products
Hydrogel catheter
Investigational
Bacterial interference
Aerobic physical training
Copyright: ROBERT A. BONOMO, M. D 2014
Copyright: ROBERT A. BONOMO, M. D 2014
MDR UTI
• ESBL E. coli +;
– 3.9% of the E coli UTI isolates were positive for ESBL and of
those, 36% were from outpatient clinics
• CRE Carbapenem-resistant Enterobacteriaceae
– Large metropolitan areas display a disproportionate
amount of CRE; almost 21% of Klebsiella pneumoniae
isolates from New York City hospitals were reported to be
carbapenem-resistant
• VRE Rates of up to 30% of VRE have been reported in
intensive care units in the United States
Copyright: ROBERT A. BONOMO, M. D 2014
ESBL and Amp C producing GNRs
• AmpC beta-lactamases are carried
chromosomally and infer inducible resistance
during antibiotic exposure to penicillins,
narrow-spectrum cephalosporins and
cephamycins
• Present in Enterobacter, Citrobacter freundii,
Serratia, Morganella morganii, Providencia,
and Pseudomonas aeruginosa---recurrence
Copyright: ROBERT A. BONOMO, M. D 2014
Risk factors for MDR UTIs
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Age older than 60 years,
Prior UTI history or
Chronic medical conditions,
Recent hospitalizations or antibiotic
treatment
• Recent travel
Copyright: ROBERT A. BONOMO, M. D 2014
Why are ESBLs in UTIs bad?
• A series of nonhospitalized patients with UTIs
secondary to ESBL-producing E coli strains
showed that 5 of 37 (20%) patients became
bacteremic, requiring hospitalization because of
treatment with inadequate initial empiric rx.
• In one study, 4.1% of community-onset
bacteremias were caused by ESBL-producing E
coli, and these were associated with a mortality
rate of 21.1%.
Copyright: ROBERT A. BONOMO, M. D 2014
MDR UTI E. coli CTX-M
• Enterobacteriaceae that produce CTX-M blactamases, which are the most commonly
encountered ESBL isolates in the outpatient
setting, also carry concurrent resistance
genes to fluoroquinolones, aminoglycosides,
and sulfonamides
• This cross-resistance is especially prominent
in urinary isolates
Copyright: ROBERT A. BONOMO, M. D 2014
Rx in MDR
• For ESBLs complicated cass
– Ertapenem; preferred empiric treatment for community
and HA E. coli ; spares beta-lactam inhibitor
combinations targeted for Pa and Antipseudomnal
cephalosporins
– Fosfomycin
– Nitrofurantoin
– Oral ceph AND amox/clavu acid, 875 mg po bid (in
vitro data only)
• For CRE
– Amikacin, polymyxin B, combos
– Tige (poor clearance)
Copyright: ROBERT A. BONOMO, M. D 2014
Rx VRE
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Fosfomycin, 3 g po sachet in 3–4 oz of water x1 (more?)
Nitrofurantoin, 100 mg po bid
Doxycycline, 100 mg po bid
Ampicillin, 1–2 g IV q4h and gent??, 1 mg/kg IV q8h or
streptomycin for synergy (Enterococcus faecalis)
Linezolid, 600 mg po/IV bid
Daptomycin, 4–6 mg/kg IV q24h
Tigecycline, 100 mg IV as first dose, and then 50 mg
daily thereafter
Quinupristin/dalfopristin, 7.5 mg/kg IV q8h
(Enterococcus faecium only)
Copyright: ROBERT A. BONOMO, M. D 2014
Fosfomycin
• Uncomplicated UTIs: Fosfomycin is a cell wall
inhibitor and a bactericidal antibiotic with
broad-spectrum activity that has excellent
activity in the urinary tract.
• A recent meta-analysis illustrated the
noninferiority of fosfomycin to comparators
in clinical outcomes, such as eradication of
infection, relapse, and reinfection.
Copyright: ROBERT A. BONOMO, M. D 2014
NTF
• Nitrofurantoin can achieve good urine and
bladder concentrations, but does not achieve
adequate serum or tissue levels to serve as
treatment for pyelonephritis, prostatitis, or
other severe disease.
Copyright: ROBERT A. BONOMO, M. D 2014
Tige and Polymyxins vs Ags
• Tigecycline and polymyxin do not have good
clearance in the urine.
• Renal clearance of tige in a patient with normal
renal function is noted to be 10% to 20%
• Polymyxin B urinary excretion is even lower,
because only 4% of is excreted unchanged in the
urine.
• Aminoglycosides are more effective in clearing
bacteriuria than polymyxin B or tigecycline
Copyright: ROBERT A. BONOMO, M. D 2014
Novel Therapies
• CRE and KPCs. P. aeruginosa
– Avibactam and ceftazidime or aztreonam;
– MK-7655 and imipenem
– RPX7009 and biapenem
– Ceftolozane (CXA-101) and tazobactam [CXA
201]-- P aeruginosa and other ESBL-carrying
organisms
– Plazomicin
– BAL30072; Acinetobacter is still a challenge
Copyright: ROBERT A. BONOMO, M. D 2014
Conclusions
• Complicated UTI syndromes still present a
significant challenge
• Understanding pathophysiology may lead to
better therapuetics
• Best antimicrobial choices require an
understanding of pathogen and
pathophysiology