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Alex SorianoHospital Clínic of Barcelona
Present i futur en la era dels multi-resistents iexperiència clínica real a l’Hospital Clínic
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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
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Evolución trimestral de E. coli y K. pneumoniae resistentes a cefalosporinas de 3ª generación en el HCB
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50
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150
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(1/1/05 –31/12/17)
Nºpa
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2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
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168,0528333
137,1091384 136,9121931
157,7456047
192,0260748
236,6831174
259,7722489
245,4816232
292,1264774
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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
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Evolución trimestral de P. aeruginosa multi-resistente en el HCB
020100
(31-12-2017)
171615141312111009080706050403
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05
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(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
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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.
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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
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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
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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
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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
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
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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)
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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
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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
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Zhanel GG, et al. Drugs 2013; 73: 159-177
ceftazidima
avibactam
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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
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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
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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
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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
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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
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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
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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
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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
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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%
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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
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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
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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
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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
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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
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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
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*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
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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
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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