Present i futur en la era dels multi-resistents i ...

Alex SorianoHospital Clínic of Barcelona

Present i futur en la era dels multi-resistents iexperiència clínica real a l’Hospital Clínic

Indice

1. Necesidad de alternativas en el tratamiento de enterobacterias productoras de BLEE

2. Mecanismo de acción de CAZAVI y actividad frente a enterobacterias

3. Situación actual del tratamiento de las enterobacterias productoras de carbapenemasas

4. Utilización de CAZAVI como tratamiento empírico en áreas de alta prevalencia de enterobacterias productoras de carbapenemasas

Evolución trimestral de E. coli y K. pneumoniae resistentes a cefalosporinas de 3ª generación en el HCB

0

50

100

150

200

250

300

(1/1/05 –31/12/17)

Nºpa

cient

es

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

168,0528333

137,1091384 136,9121931

157,7456047

192,0260748

236,6831174

259,7722489

245,4816232

292,1264774

0

50

100

150

200

250

300

350

2009 2010 2011 2012 2013 2014 2015 2016 2017

nº vi

ales/1

000 e

stanc

iasViales (500+1000) de meropenem por 1000 estancias

0

10

20

30

40

50

60

1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3 1 3

Evolución trimestral de P. aeruginosa multi-resistente en el HCB

020100

(31-12-2017)

171615141312111009080706050403

05

1015202530354045

(1/1/09 – 31/12/17)

2009 2010 2011 2012 2013 2014 2015 2016 2017

Evolución trimestral de K. pneumoniae y otras enterobacterias resistentes a carbapenems en el HCB

Cantón R et al. Antimicrobial susceptibility trends and evolution ofisolates with ESBL among gram-negative organisms recovered

during the SMART study in Spain (2011-2015). Rev Esp Quimio 2018; 31: 136-145

microorganismo AMC % R(CMI >8)

PTZ % R (CMI>16)

BLEE-E. coli (n=2857)

BLEE-K. pneumoniae (n=570)

20.3

49.3

22

62.7

SMART: study for monitoring antimicrobial resistance trends. Participación de 11 centros españoles.

Gutiérrez B et al. A multinational,

pregistered cohortstudy of β-

lactam/β-lactamaseinhibitor

combinations fortreatment ofbloodstream

infections due toESBL

EnterobacteriaceaeAntimicrob Agents

Chemother2016;60:4159.

N (%)

627462 (74)117 (19)

48 (8)

285 (45)94 (15)

248 (40)

213 (34)

156 (25)152 (24)63 (10)

225 (36)31 (5)

28% de cepas R a BL-IBL

Harris P, et al. Effect of PTZ vs MER on 30-d mortality for patientswith E. coli or K. pneumoniae BSI and ceftriaxone resistance a

randomised controlled trial. JAMA 2018; 320: 984-94

dentro de las primeras 72h desde el HC (PTZ-S)

E. coli : 86.5%Foco urinario : 60.9%

N=191 N=188

Harris P, et al. Effect of PTZ vs MER on 30-d mortality for patientswith E. coli or K. Pneumoniae BSI and ceftriaxone resistance a


Harris P, et al. Effect of PTZ vs MER on 30-d mortality for patientswith E. coli or K. Pneumoniae BSI and ceftriaxone resistance a


12.3%*

3.7%*

by the day of randomization 40% (the same in both arms) of the patients had clinical and microbiology resolution

Charlson score2 (1-4)

2 (1-4)

* aOR (Charlson and urinary source): 4.3 (CI95%: 0-8.3)

% su

rviva

l

Vital organ invasion by growing bacteria

Determinants of mortality in SEPSIS

Host inflammatoryresponse

Early active antibiotic (PK/PD)

Bundles of measures

Host co-morbidity

Early mortality ( ≤ 5 days)Late mortality

(30 days)

Source control (surgery, catheter)

Efecto de la administración empírica de un carbapenem en pacientes con bacteriemia por una enterobacteria (E. coli, K.

pneumoniae, Enterobacter spp) resistente a C3ªG. Registro de bacteriemia del HC 2000-2017

antibióticoempírico

Mortalidad30-d/total (%) P

no carbapenem

carbapenem

15/71 (21.1)

11/178 (6.2)

bacteriemia por enterobacterias de foco urinario

- no shock- shock

6/51 (11.8)9/29 (45)

- no shock- shock

5/146 (3.4)6/32 (18.8)

0.0005

0.040.02

Indice





Zhanel GG, et al. Drugs 2013; 73: 159-177

ceftazidima

avibactam

Ehmann DE, et al. J Biol Chem 2013; 39: 27960-71

x105

x104

acilación (M-1s-1)

x103

x103

x103

T > Ct 100%

ESBLKPC

AmpC (E)AmpC (PA)

OXA 48

A

C

D

40+1082+6

t permanencia (min)

300+206+2

1000+300

Sternbach N, et al. Efficacy and safety of Ceftazidime-Avibactam: a systematic review and meta-analysis.

J Antimicrob Chemother 2018; 73: 2021-9

Indications approved by EMA:1. complicated UTI2. complicated IAI3. HAP or VAP4. Infections due to aerobic Gram-negative organisms in

patients with limited treatment options

Kazmierczak KM, et al. In vitro activity of Ceftazidime-Avibactamagainst Enterobacteriaceae collected in Europe: INFORM 2012-15.

J Antimicrobi Chemother. 2018;73:2782–88

Enterobacteriaceae(n=24,750)* MIC90 (mg/L) Susceptibility (%)

CAZ–AVICeftazidimeCefepimeAztreonamPiperacillin–tazobactamMeropenemAmikacinColistin (n=13906)

0.564

>1664

1280.12

8>4

99.474.878.775.077.397.293.682.8

* 96 centres in 18 European countries

Carmeli Y, et al. Ceftazidime-avibactam or BAT in patients withceftazidime-resistant Enterobacteriaceae and P. aeruginosa cUTI orcIAI (REPRISE): a randomised, pathogen-directed, phase 3 study.

Lancet Infect Dis 2016;16:661–73

Microbiological response rate (%)

126/154 (82%) 94/148 (64%)

118/144 (82%)88/137 (64%)

cUTI+cIAI

cUTI

140/154 (91%)135/148 (91%)

132/144 (92%)129/137 (94%)

n/N (%) n/N (%)

cIAI

Clinical response rate (%)0 20 30 40 50 60 70 10080 9010

8/10 (80%)6/11 (55%)

0 20 30 40 50 60 70 10080 9010

8/10 (80%) 6/11 (55%)

Clinical response rate (90% CI) at TOCPer-patient favourable microbiological

response rate* (95% CI) at TOC

Ceftazidime–avibactam BAT

• 96% of BAT was a carbapenem in monotherapy• Clinical cure rates at TOC were similar between treatment groups• Favourable per-patient microbiological response rates were numerically higher with

ceftazidime–avibactam than BAT in the cUTI population. 28-d mortality CAZVI 2.1% BAT 2.2%

• The number of cIAI patients in this study was small, although results were favourable towards ceftazidime–avibactam

Indice





Tumbarello M, et al. Infections caused by KPC-producing K. pneumoniae: differences in therapy and mortality in a MC-study.

J Antimicrob Chemother 2015; 70: 2133–2143

* carbapenem dose was not specified

17%

33%

combinations (colistin, gentamicin, tigecycline, carbapenem) vs. monotherapy in 14d-mortality

meropenem 2g/8h in 3h infusion + ………… disregarding the source or severity of infection

Shields RK et al. Ceftazidime-avibactam is superior to othertreatment regimens against carbapenem-resistant K. pneumoniae

bacteremia. Antimicrob Agents Chemother 2017;61: e00883-17

30-d

ay cl

inica

l suc

cess

30-d mortality (%): 32 30 32

97% KPC, 100% R to meropenem (merop dose was not provided)N=109

Gutierrez-Gutierrez et al. Effect of appropriate combination therapy onmortality of patients with bloodstream infections due to CP

Enterobacteriaceae (INCREMENT): a retrospective cohort studyLancet Infect Dis 2017; 17: 726-34



Increment score:Severe sepsis/septic shock------- 5Charlson sc ≥2 ------------------------ 3Source other than UTI or biliar--- 3Inappropriate tx------------------------ 2

55%

38%

Benattar, et al. The effectiveness and safety of high-dose colistin: prospective cohort study.

Clin Infect Dis 2016; 63: 1605-12

RIFLE >1: SCr increased ≥2 times orCrCl decreased ≥50% of baseline

* high-dose: 9 MU/d, low-dose: 4 MU/d

Tumbarello M, et al. Infections caused by KPC-producing K. pneumoniae: differences in therapy and mortality in a MC-study.

J Antimicrob Chemother 2015; 70: 2133–2143

* carbapenem dose was not specified

17%

combinations (colistin, gentamicin, tigecycline, carbapenem) vs. monotherapy in 14d-mortality

meropenem 2g/8h in 3h infusion + ………… disregarding the source or severity of infection

Wiskirchen et al. Efficacy of Humanized Carbapenem andCeftazidime Regimens against E OXA-48 Carbapenemase in a Murine

Infection Model. Antimicrob Agents Chemother 2014; 58: 1678-83

DORIPENEM 2g (4h inf) q8h

KPMIC* 0.03

ƒT>MIC100%

KPO-480.38**

100% 95% 85% 70%

CFO-48

1

100%

ECO-48+ESBL

2

95%

KPO-48+ESBL

2

95%

KPO-48+ESBL

3

KPO-48+ESBL

6

KPO-48+TEM

8

* inóculo 105 UFC/mL** cepa isogénica con un plásmido OXA-48*** inóculo empleado en el modelo animal 108 UFC/mL

Smith KP, et al. The inoculum effect in the era of MDR: minordifferences in inoculum have dramatic effect on MIC determination.

Antimicrob Agents Chemother 2018; 62: 361-9

Indice





*risk per each additional siteCI, confidence interval; OR odds ratio.

Risk factor OR (95% CI), P-value Score

1. Admission to ICU 1.65 (1.05-2.59), 0.03 2

2. Invasive abdominal procedures 1.87 (1.16-3.04), 0.01 3

3. Chemotherapy/radiation therapy 3.07 (1.78-5.29), <0.0001 4

4. Colonisation at sitebesides stool* 3.37 (2.56-4.43), <0.0001 5 (per site)

Giannella M, et al. Risk factors for CR-K. Pneumoniae bloodstreaminfections among rectal carriers: prospective observational

multicentre study. Clin Microbiol Infect 2014;20:1357-62

Kazmierczak KM, et al. In vitro activity of Ceftazidime-Avibactamagainst P. aeruginosa collected in Europe: INFORM 2012-15.

J Antimicrobi Chemother. 2018;73:2777–81

P. aeruginosa (n=5,716)* MIC90 (mg/L) Susceptibility (%)

CAZ–AVICeftazidimeCefepimeAztreonamPiperacillin–tazobactamMeropenemAmikacinColistin (n=3926)

8641632

>128>8322

92.476.978.14.369.172.584.399.6

* 96 centres in 18 European countries

At the country level, susceptibility to CAZ–AVI

ranged from 74.6% to 99.6%, with decreased susceptibilities

only observed in countries where MBLs are more frequently encountered

Score* <7 (48) ≥7 (46)

infection

Infection by no KPC

Infection by KP-KPC

44 (96%)

5 (10.9%)

39 (84.8%)

32 (67%)

29 (60.4%)

3** (6.2%)

standardprotocol***

ceftazidime–avibactam + …

empiricaltherapy

*94 colonised patients with KP-KPC**Only 1 episode of bacteremia***Except in cases with a severe infection (Pitt score >4, shock)KPCKP, Klebsiella pneumoniae carbapenemase-producing K. pneumoniae.

Cano A, et al. Risks of Infection and Mortality Among PatientsColonized With Klebsiella pneumoniae Carbapenemase–ProducingK. pneumoniae: Validation of Scores and Proposal for Management.

Clin Infect Dis 2018; 66: 1204-10

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