management of bsi due to gram-negatives according to
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Management of BSI due to
Gram-negatives according to
patient, source and MIC
Pilar Retamar Gentil
Department of Infectious Diseases and Clinical Microbiology
Hospital Universitario Virgen Macarena
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Case 1
71 year-old lady
Background:
No allergies,
High blood presure, dyslipemia.
Poliarthrosis, left Knee protesis.
Neurogenic bladder (spine arthrosis) pending for
surgery.
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Case 1
August 2013: Internal medicine admission: UTI.
GP treated with 3 weeks of amoxicillin-clavulanic (no urine culture).
Levofloxacin 500 iv/12 h.
Blood and urine cultures negative.
Discharge after 7 days with a one week of AB at home.
September 2013: fever and dysuria.
No leuKocytosis. CR-protein: 153. Urine culture taken (see next slide…).
Discharge with cephuroxime for one week.
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Case 1:
a ring from the micro lab…!!!!!!!
*CLSI breakpoints
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Which mechanism would explain this
antibiogram…..
A desrepressed AMPc plus and a porin loss?
A ESBL plus a AMPc?
Anything more?
A carbapenemase?
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Which mechanism would explain this
antibiogram…..
A desrepressed AMPc plus and a porin loss?
A ESBL plus a AMPc?
Anything more?
A carbapenemase?
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Carbapenem-Resistance
Livermore KJIM 2012.
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Case 1:
*CLSI breakpoints
OXA-48
CTX-M15
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Case 1
We called the patient, who is febrile and asked her to come to the
hospital. Blood culture was taken.
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Which of the following are risk factors for
developing an infection by a carbapenemase
producer microorganism?
Coming from an endemic country
Presenting recurrent UTI
All of them
Previous AB use
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Which of the following are risk factors for
developing an infection by a carbapenemase
producer microorganism?
Coming from an endemic country
Presenting recurrent UTI
All of them
Previous AB use
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Risk factors…..
PROBABILITY
PREVALENCE
CR Enterobacteriaceae: ECDC March 2013
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Endemic countries
LTCF
Waste water
UTI, IAI
Invasive procedures
Previous AB
Respiratory TI, VAP, catheter (outbreaks)
Imported cases
Muñoz-Price Lance ID 2013-Livermore KJIM 2012- McGuin EID 2009- Scotta AAC2011
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And regarding the outcome…we
should consider…
using colistin?
treating the patient at the ICU?
forget about it…there is nothing to do.
a combination therapy?
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And regarding the outcome…we
should consider…
using colistin?
treating the patient at the ICU?
forget about it…there is nothing to do.
a combination therapy?
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OR for mortality: 0.07 (95%CI: 0.009-0.71)
p=0.02
AAC 2012
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Tumbarello et al, CID 2012
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Daikos AAC 2014
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Which treatment would you initiate in
this patient?
Amikacyn 1 gr qd iv
Meropenem 1 gr/8 hrs in 30 mins + Fosfomycin 4
gr/6h
Meropenem 1 gr in 30 mins + 2gr/8 hrs in 3 hrs
plus Amikacyn 1 gr qd iv
Tygeciclin 50 mg/ 12h + Amikacyn 1 gr qd iv
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Which treatment would you initiate in
this patient?
Amikacyn 1 gr qd iv
Meropenem 1 gr/8 hrs in 30 mins + Fosfomycin 4
gr/6h
Meropenem 1 gr in 30 mins + 2gr/8 hrs in 3 hrs
plus Amikacyn 1 gr qd iv
Tygeciclin 50 mg/ 12h + Amikacyn 1 gr qd iv
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Co
nc
en
tra
tio
n
Time
t1/2
Cmax
PK/PD predictors of efficacy
CMI
ABC/CIM
Cmax/CIM
%Texposition>CIM
Aminoglicosydes
Fluorquinolones
Tetraciclins
Glicopetids
Fluorquinolones
Linezolid
Macrolides
Beta-lactams ESCMID Online Lecture Library
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Meropenem (treated patients)
Chongua Clin Pharmacol 2006
Bactericide effect
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Different dosing regimens of
meropenem
Daikos el al. CMI 2011
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Combined therapy for CP-KP
Which is the best combination?
Meropenem 2 g/8h extended infusion
Perhaps if MIC <8 mg/L
(AZT for MLB, ceph for OXA-48 if susceptible)
Plus 1 or 2 of colistin, tigecyclin, fosfomycin, AG ESCMID Online Lecture Library
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79 year-old man
Background:
Urolithiasis.
3 UTIs in the previous year, no cultures (fosfomycin,
ciprofloxacyn).
Urine catheter since two months ago for urinary retention.
6 weeks ago had dysuria and took 1 week course of
cyprofloxacin.
Case 2
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At emergency: fever 39ºC and hypotension (86/44 FC 103),
Heart rate: 88 spm;
Tendernesss at the right kidney 19.000 leuKocytes, lactate 1,0.
Urine: nitrites (+)
Urine, blood culture and echo performed.
Case 2
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Which of those is not a risk factor of
developing a ESBL-Enterobacteriaceae
infection?
Previous treatment with ciprofloxacyn
Travelling to endemic areas
A respiratory source
A health-care related acquisition
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Which of those is not a risk factor of
developing a ESBL-Enterobacteriaceae
infection?
Previous treatment with ciprofloxacyn
Travelling to endemic areas
A respiratory source
A health-care related acquisition
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EARSS 2007-13. E. coli cephs R (BSI)
2007 2012
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Rodriguez-Baño CID 2012
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Italian model Duke model
Recent beta-lactams of fluoroquinolones 2 3
Previous hospitalization 3 2
Transfer from another healthcare facility 3 4
Recent history of urinary catheterization 2 5
Charlson score ≥4 2 -
Age ≥70 years 2 -
Immunosupression - 2
Italian Model Duke model
Score 3 Sensitivity ≥95% ≥94%
Specificity ≤47% ≤65%
Score 8 Sensitivity ≤50% ≤ 58%
Specificity ≥96% ≥95%
Tumbarello AAC 2011
Johnson, ICHE 2013
Predictive models for bacteraemia due to ESBL-producers
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Which treatment would have you
started in this patient?
Ciprofloxacin 400 mg/12h
Cephotaxim 2 gr/ 6h
Meropenem 1 gr iv/8h
Ertapenem 1 gr iv/24h
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Which treatment would have you
started in this patient?
Ciprofloxacin 400 mg/12h
Cefotaxime 2 gr/ 6h + Amikacin
Meropenem 1 gr iv/8h
Ertapenem 1 gr iv/24h
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Ertapenem
Useful for ESBLs (observational studies)
Lee, AAC 2012; Fong, Ann Pharmacother 2012; Collins, AAC
2012; Woo, IJID 2012
Lower ecologic (or not higher) impact on P. aeruginosa compared
to imipenem/meropenem
Sousa, JAC 2013; Nicoalu, IJAA 2012; Carmeli, DMID 2011
Risk of R development in Klebsiella, Enterobacter if boderline MIC
(0.25-0.5)?
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Case 2: day 2
Urine and blood culture
Patient stable, not fever, catheter removed.
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Day 3: stable, not fever, catheter
removed…NOW:
You complete 10 days with ertapenem.
You complete 10 days with pip/taz.
You would change to amoxicilin-clavulanic, first
iv, them oral.
You would change to oral fosfomycin.
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Day 3: stable, not fever, catheter
removed…NOW:
You complete 10 days with ertapenem.
You complete 10 days with pip/taz.
You would change to amoxicilin-clavulanic, first
iv, them oral.
You would change to oral fosfomycin.
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Prognostic impact “This patient”
Ecologic impact “The next patients”
The clinician’s dilemma...
Leibovici et al. Ethical dilemmas in antibiotic treatment. JAC 2011
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Remember….
Urine and blood culture
Patient stable, not fever, catheter removed.
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Candidates
– Betalactam-inhibitors combinations
– Cephalosporins
– Temocillin (unavailable in most countries)
– Fluorquinolones (most are R)
– (Aminoglycosides)
– (Tigecycline)
– (Fosfomycin)
– (Colistin)
Definitive therapy for ESBL BSI: Is there any carbapenem-spare option?
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Cephs therapy for ESBL
PK/PD animal data suggest…
Efficacy if T>MIC >40%
Achievable if MIC <1 mg/L
Andes, CMI 2005. MacGowan, CMI 2008
Some positive clinical data
Paterson JCM 2001. Bin, DMID 2006. Goethaert, CMI 2006.
But some (recent) doubts…
Rodríguez-Baño, CMI 2012 (severe, non UTI infections),
Chopra, AA 2012. Lee, CID 2013 (cefepime) ESCMID Online Lectu
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Rodríguez-Baño CID 2012
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BLBLI vs carbapenems Empirical
therapy cohort Definitive
therapy cohort
Death (HR,adjusted)* 0.93 (0.25-3.51) 0.76 (0.28-2.07)
Hospital stay (HR, adjusted)* 1.07 (0.3-3.0) 1.32 (0.91-1.90)
*Including propensity score
Rodríguez-Baño CID 2012
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Empirical therapy BLBLI vs carbapenems
Vardaska JAC 2013
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Definitive therapy BLBLI vs carbapenems
Vardaska JAC 2013
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Vardaska JAC 2013
Carbapenems RR (95% CI)
vs. non-BLBLI Empirical 0.50 (0.33-0.77)
Definitive 0.65 (0.47-0.91)
vs. BLBLI Empirical 0.91 (0.66-1.25)
Definitive 0.52 (0.23-1.13)
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If the patient had a peritonitis source
BSI instead of an UTI…
We could also use a BLBLI
The treatment would depend on the MIC
Who Knows…?
It depends on the surgical management
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If the patient had a peritonitis source
BSI instead of an UTI…
We could also use a BLBLI
The treatment would depend on the MIC
Who Knows…?
It depends on the surgical management
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If the patient had a peritonitis source
BSI instead of an UTI…
We could also use a BLBLI
The treatment would depend on the MIC
Who Knows…?
It depends on the surgical management
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Amox/clav (8xMIC) Pip/taz (8xMIC)
Low
inoculum
High
inoculum
ESBL-producing E. coli
López-Cerero et al, CMI 2010
CTX-M-14 SHV-12 TEM-3
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Positive blood cultures after treatment (%)
Docobo AAC 2013
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Bacteraemia due to ESBLEC treated with PTZ N=39
Other source N=28
Low MIC Mortality 0/11b
Intermediate MIC Mortality 3/8 (37.5%)c
High MIC Mortality 4/9 (44.4%)d
Urinary tract N=11
Low MIC Mortality 0/7a
Intermediate MIC Mortality 0/2
High MIC Mortality 0/2
0
20
40
60
<1 1 2 4 8 16 32 64 128 256
Nu
mb
er
of
iso
late
sMIC (mg/L)
PTZ
Retamar AAC 2013
MIC distribution
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Patient Empirical drug, dose
(MIC in mg/L)
Age, gender Comorbidity Source SIRS Definitive therapy Survival in days
1 PTZ, 4.5 g/8h (4) 86, M None Biliary tract Severe sepsis None 2
2 PTZ, 4.5 g/8h (8) 58, M Renal insuff Biliary tract Sepsis Imipenem 11
3 PTZ, 4.5 g/6h (8) 78, M DM, CPD Wound infection Sepsis None 2
4 PTZ, 4.5 g/8h (16) 57, F Cancer, cirrhosis Primary peritonitis Sepsis PTZ 11
5 PTZ, 4.5 g/6h (64) 55, M Cancer Secondary peritonitis Severe sepsis Imipenem 5
6 PTZ, 4.5 g/6h (128) 70, M DM, cirrhosis Pneumonia Sepsis Imipenem 27
7 PTZ, 4.5 g/6h (256) 33, M Cancer Wound infection Septic shock Imipenem 20
8 AMC, 2 g/8h (4) 80, F None Biliary tract Septic shock Ertapenem 10
9 AMC, 2 g/8h (8) 84, F Cancer Unknown Severe sepsis AMC 8
10 AMC, 2 g/8h (8) 74, M DM, CPD Pneumonia Severe sepsis AMC 14
11 AMC, 1 g/8h (16) 20, M Severe trauma Pneumonia Sepsis None 2
12 AMC, 2 g/8h (32) 61, M Cirrhosis Unknown Septic shock AMC 24
Retamar et al. AAC 2013
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BLBLI for ESBL. Conclusions
Not so solid background for not using BLBLI
Amox/clav and pip/taz may not be equivalent
BLBLI may be an alternative to carbapenems for some
patients:
E. coli
Urinary tract (including bacteraemic) infections
Piperacillin/tazobactam: MIC low enough??
More data needed for Klebsiella spp, other sources,
borderline MIC (pip/taz)
Main potential use as definitive therapy
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Case 3
78 year-old man
Background:
No allergies, diabetic.
August 2013: haematuria (cyprofloxacin 7 days
twice), studied: urothelial carcinoma.
November 2014: radical cystectomy.
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Postoperative complications: ICU
Day 5: Fever:
Pseudomonas aeruginosa catheter BSI (R to
ciprofloxacyn)
Treated with piperacillin-tazobactam for 14 days.
Catheter removed.
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Postoperative complications:
urologic ward
Day 10:
Supurative wound and drainage.
Abdominal-CT: subcutaneous collection.
Surgical drainage.
Pip-taz.
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Case 3
Day 11: Fever 16546 leukocytes (89% WC), RC-protein:149.
Physical examination:
BP 97/54 FC 103
Right Yugular Catheter OK
Thorax OK
Abdomen: still a litle painful.
Results from wound culture… (next slide)
Blood culture taken
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Case 3
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Which of those is a risk factor for
Acinetobacter baumannii BSI?
A previous surgery
A previous AB treatment
A central venous catheter
All of them ESCMID Online Lecture Library
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Which of those is a risk factor for
Acinetobacter baumanbii BSI?
A previous surgery
A previous AB treatment
A central venous catheter
All of them ESCMID Online Lecture Library
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Risk factors for AB BSI
Lee Journal Infection 2010
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Cisneros JM et al. CMI 2005
Logistic regression:
Hospital>500 beds OR:6.61; (95% CI: 1.8–23.2)
Antimicrobial treatment OR:4.36; (95% CI: 1.6–11,5)
Previous surgery OR:2.02; (95% CI: 1.1–3.8)
Urinary catether OR:2.77; (95% CI: 1.1–3.8)
Risk factor for nosocomial Imip-R AB
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Risk factors for XDRAB BSI
Chan Plos One 2014 ESCMID Online Lectu
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CR A. baumannii
AmpC cromosómico
Carpamenemasas:
OXA 51
OXA 23, 40, 58
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Case 3
Acinetobacter baumannii
*suceptible to tigecycline
BLOOD CULTURE
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Which treatment would you start in this
patient?
Monotherapy with Colistin
Monotherapy with Tigecycline
Imipenem + amikacin
Colistin + Tigecycline
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Which treatment would you start in this
patient?
Monotherapy with Colistin
Monotherapy with Tigecycline
Imipenem + amikacin
Colistin + Tigecycline
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Which treatment would you start in this
patient?
Monotherapy with Colistin
Monotherapy with Tigecycline
Imipenem + amikacin
Colistin + Tigecycline
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Colistin for Treating MDR Acinetobacter BSI
30th day mortality predictors:
Lim et al JKMS 2011
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CMI 2009
“…..data from the small number (four) of relevant human studies suggest
non-inferiority of colistin monotherapy as compared with combination therapy.
In conclusion, microbiological studies suggest superiority of colistin
combination treatment, which is in contrast to preliminary data from studies
in humans….”
“….. available data concerning heteroresistance have provided some scientific
arguments in support of the possible advantages of combination regimens in
eradicating resistant subpopulations”.
Durante-Mangoni CID 2013 (Rifampicin)
Pogue Exp Rev In Ther 2013 (Review)
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Which dose of colistin would be the
most appropiate?
Colistin 4.5 MU/ 12h
Colistin 3 MU/8h
Colistin 4.5 MU loading dose + 3 MU/8h
Colistin 9MU loading dose + 4.5 MU/12h
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Which dose of colistin would be the
most appropiate?
Colistin 4.5 MU/ 12h
Colistin 3 MU/8h
Colistin 4.5 MU loading dose + 3 MU/8h
Colistin 9MU loading dose + 4.5 MU/12h
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Plachouras AAC 2009
Garouski AAC 2011
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Acute Kidney Injury Associated
With Colistimethate Sodium Therapy
Dalfino CID 2012
Loading dose of 9 MU and a 9-MU twice-daily fractioned
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Conclusions
ESBLs
Lower tract UTI: fosfomycin, amox/clav, nitro
Serious infections
Carbapenems but…
BLBLI, temocillin?
AG for UTIs
Carbapenemase producers
Serious infections: combined therapy
Optimized carbapenem + 1-2 active drugs
XDR Acinetobacter baumannii/Pseudomonas aeruginosa
Optimized Colistin + 1-2 drugs (if heterorresistance)
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Pipeline
Plazomicin (neoglycoside)
Avibactam (beta-lactamase inhibitor)
Not class B
With ceftazidime, ceftaroline, aztreonam
Ceftolozone-tazobactam (only ESBLs, AmpC)
Omadacycline (aminomethylcycline)
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Ongoing projects
INCREMENT project (REIPI-ESGBIS)
Retrospective cohorts
BSI cases due to ESBL or carbapenemases
30 centers from 18 countries
FOREST project
RCT IV fosfomycin vs meropenem for ESBL-Ec
bacteraemic UTI
www.incrementproject.org
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pilaretamar@hotmail.com
Thanks for coming and enjoy!
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