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