Management of BSI due to Gram-negatives according to

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

ESCMID Online Lecture Library

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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

re Library

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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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Who Knows…?



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Who Knows…?



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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

re Library

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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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patient?



Imipenem + amikacin



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patient?



Imipenem + amikacin



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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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[email protected]

Thanks for coming and enjoy!


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Documents

Management of BSI due to Gram-negatives according to