Nous reptes en l'era de les multi resistències:

orientats al focus

Isabel Ruiz CampsServei de Malalties infeccioses

Hospital Universitari Vall d’Hebron

Infecció en el pacient immunocompromès

Agraïr ajuda Dra. Gudiol en preparaciód’aquesta presentació.

Disclosure

• Research funding: GSK• Honoraria: Astellas, Celgene, Gilead, MSD,

Pfizer• Advisory board: Chiesi, Astellas, Gilead, Pfizer• Consultancy: Gilead, Pfizer, Ferrer, Aspen• Shareholder: no disclosures

2

Index

• Consideracions generals: definició de població

• Factors de risc MDR/mortalitat• Solucions• Conclusions

Infecció

FàrmacHoste

Efecte advers

Malaltía de base

comorbilitats Fàrmacs previs

Edad

Dra. I. Ruiz Camps

Onco-hematològics

TOS

Immunossupresors

crítics

altres

Immunocompromesos

Most risk factors of antimicrobial resistance are the same for non-immunosuppressed and

immunocompromissed population.

Infections due to MDR organisms usually occur in complex patients who need prolonged antibiotic therapy and prolonged hospitalization and who

often undergo invasive procedures

Can be different depending on population studied

May vary depending on the type of organism

MDR bacterial infections

Risk factors for resistances

• Previous exposure to broad-spectrum antibiotics (cephalosporins, carbapenems, fluoroquinolones)

• Baseline caracteristics: Serious illness, end-stage disease, sepsis, pneumonia, immunosupression, >70 years, Charlson index >3, SOT, neutropenia…)

• Epidemiological background: Prolonged hospital stay and/or repeated hospitalizations, ICU stay, local epidemiology or outbreak, travel from high endemic area (Central western Asia), nosocomial infection

• Prior colonization: gut ESBL, CRE or endotracheal Pseudomonas• Indwelling devices: Urinary catheters, gastrostomy or jejunostomy,

nasogastric tube, CVC, mechanical ventilation, hemodialysis

1.- Hussein K et al. Infect. Control Hosp Epidemiol 2009; 30: 666-671/ 2.- Hussein K. J Hosp Infect 2013; 83: 307-313/ 3.-Baker TM: Leukemia &Lymphoma 2016; 57 (10): 2245-2258/ 4.- Satlin MJ. Clin Infect Dis 2014; 58: 1274-83/ 5.- DumfordDM. Infect Clin N Am 2016; 30: 465-489/7.- Gudiol C. JAC 2011; 66:657-63 / 8.- Baker TM: Leukemia &Lymphoma 2016; 57 (10): 2245-2258/ 9.- Basetti M. Expert Rev Anti-Infect Ther 2016 (accepted 21/10)

Risk factors for mortality• Inappropiate initial ATB therapy• Time to adequate ATB therapy >48h (OR: 2.36; 95% CI,

0.62-8.93; p=0.008)2

• BSI with MDR organism (OR: 3.6; 95% CI, 1.40-9.32; p=0.008)3• Other factors:

– ICU admission– Solid Tumor– GVHD– Increased severity of illness (Charlson comorbidity index,

SOFA,...)

1.- Baker TM: Leukemia &Lymphoma 2016; 57 (10): 2245-2258 /2.- Gudiol C. JAC 2011; 66:657-63 /3.- Macesic N. Traspl Infect Dis2014; 16:887-96 /4.- Dumford DM. Infect Clin N Am 2016; 30: 465-489/ 5.-Moreno A. Am J Transplant 2007; 7: 2579-86 /6.- Lupei MI Surg Infect 2010; 11:33-9 /7.- Kitazono H. Clin transplant 2015; 29:227-32.

Location Period GNB Incidence Overall mortality

Italy1 2000-2007 E. coli 42% 21%

Spain2 2006-2008 E. coli 13% 35%

Pakistan3 1999-2006 Enterobacteriaceae 24%-56% NR

Korea4 2008-2009 E. coli/K. pneumoniae 24% 45%

Korea5 2010-2012 E. coli 27% 22%

Italy6 2009-2012 Enterobacteriaceae 36.9% NR

Bacteremia due to ESBL-producing Enterobacteriaceae in cancer patients

1Trecarichi. J Infect 2009, 2Gudiol. J Antimicrob Chemother 2010, 3Irfan S. BMC Infect Dis 2008,4Kang. Ann Hematol 2012, 5Ha. International Journal Antimcrobial Agents 2013, 6Trecarichi. Clin Microbiol Infect 2015

Ref. Period Location Incidence Overall mortality

Casseli1 2000-2008 Italy 31.% 35.8%

Trecarichi2 2006-2008 Italy 71.1% 41.1%

Cattaneo3 2004-2010 Italy 33.3% 36.4%

Trecarichi4 2009-2012 Italy 69.7% NA

Averbuch5 2014-2015 Europe 29.2% NA

Kim HS6 2011-2016 Korea 36.1% 64.3%

Bacteremia due to MDR Pseudomonas aerugionsa in patients with hematological diseases

1Caselli D. Haematologica. 2010; 2Trecarichi EM. Haematologica. 2011; 3Cattaneo C. Ann Hematol. 2012; 4Trecarichi EM. ClinMicrobiol Infect. 2015; 5Averbuch D. Clin Infect Dis. 2017; 6Kim HS. BMC Infect Dis. 2017.

Location Patients CRE HSCT NTP Mortality

NYC1 18 K. pneumoniae 6 13 56%

E. cloacae

Israel2 8 K. pneumoniae 5 7 50%

Maryland3 6 K. pneumoniae 4 NA 100%

Rome4 26 K. pneumoniae NA 19 57.6%

NYC5 43 K. pneumoniae 18 43 51%

E. cloacae, E. coli

Greece6 50 K. pneumoniae NA 50 50%

Spain7 31 Kp. K. oxytoca NA 24 45.2%

S. marces, E. cloac

Italy8 14 K. pneumoniae NA 12 70%

Italy9 161 K. pneumoniae 26 132 52.2%

Bacteremia due to carbapenem-resistant Enterobacteriaceae in patients with hematological diseases and HSCT recipients

1Satlin. Leuk Lymph 2013; 2Zuckerman. BMT 2011; 3Snitkin. Sci Transpl Med 2012; 4Pagano. Emerg Infect Dis 2015; 5Satlin. J Infect 2016;6Tofas . Int J Antimicrob Agents. 2016; 7Caston. Int J Infect Dis 2017, 8Micozzi A. BMC Infect Dis 2017; 9Trecarichi. Am J Hematol 2017

Index

• Consideracions generals: definició de població

• Factors de risc MDR/mortalitat• Solucions• Conclusions

Optimitzaciótractament

empíric

Optimitzartractament

dirigit

DesescaladaDuradaPK/PD

Control focus

infecció

EscaladaDesescalada

En pacients immunocompromesos ambcancer, TPH i crítics, l’administració d’un antibiotic empíric adequat és esencial, especialment durant els episodis de neutropenia febril.

• 394/1.615 (24%) received IEAT (87% followed IDSA guidelines).

• Overall mortality higher in patients with GNB BSI and IEAT (36% vs 24%, p=0.004).

• Only infections due to P. aeruginosa experienced increased mortality when receiving IEAT (48% vs 31%; p=.027).

• Independent risk factors for mortality in PA BSI were IEAT (OR 2.41; 95% CI 1.19-4.91), shock at onset (OR 4.62; 95% CI 2.49-8.56) and pneumonia (OR 3.01; 95% CI 1.55-5.83).

Inappropriate empirical antibiotic therapy in high-risk neutropenic patients with bacteremia

Martínez-Nadal G. Clin Infect Dis 2019 (in press)

• 14% due to MDRGNB

• IEAT was significantly

higher (39% vs 7%,

p

Before choosing an empirical ATB therapytake into account:

• Local bacterial epidemiology and resistance patterns in each hospital, unit and geographical area

• previous history of colonization or infection by resistant pathogen (travelling to endemic areas- Southern Asia)

• other risk factors for infection due to resistant pathogens

• Other patient-related factors that may predict a complicated clinical course (advanced age, inpatient status, co-morbidities, shock and localized infection)

Hauríem de fer un frotis rectal alsnostres pacients per tal de saber si colonitzats per un MDR?

Cattaneo C. Ann Hematol 2018

Multicenter, prospective, observational study (on behalf of SEIFEM)

Overall incidence of MDR rectal colonization: 6.5% (144/2.226).

CR 3.8% > ESBL-P 2.9% > 0.4% VRE.

37/144 (25.7%) colonized patients developed bacteremia, 62.2% (16% of

the overall cohort) due to the same organism (MDRrel BSI).

MDRrel BSI rate higher for CR bacteria (15.6%) and ESBL-E (14.1%).

Median: 12 days from colonization. 87% during neutropenia.

3-month survival lower for patients colonized by CR bacteria (83.6%), and

VRE (77.8%), than those colonized by ESBL-P bacteria.

Nesher L. Transpl Infect Dis 2015

Hauríem de fer un frotis rectal alsnostres pacients per tal de saber si colonitzats per un MDR?

Frotis rectal si centre amb tases

elevades de resistència a

carbapenems I BLEEs

Si colonitzats iniciar tractament

amb cobertura en front aquest

microorganismes.

ESCALATION DE-ESCALATION

Empirical antibiotic therapy

Averbuch D. Haematologica 2013

1. Presentació clínica no complicada

2. No FR de multiresistència

3. Centres amb baixaprevalença de resistències

1. Presentacions clíniquescomplicades

2. FR de multiresistència3. Centres amb baixa

prevalença de resistències

Adaptada de Dra. Gudiol

Piper-Tazo/Cefepime+amikacina

Differences between neutropenic patients with hematologicalmalignancies and solid tumors with BSI

Hematological malignancies Solid tumors pn = 493 (%) n = 86 (%)

- Endogenous bacteremia 51.3% 26.7%

Gudiol C. ECCMID 2019. Poster 2427.

Retrospective international multicenter observational study (33 centers

worldwide).

1.217 episodes of PA BSI in neutropenic onco-hematological patients

(2006-2018).

311 episodes due to MDR strains (25.6%).

Fluoroquinolone prophylaxis RF for multidrug resistance acquisition.

Initial empirical combination therapy was superior in adequateness

(91.4% vs 76.7%, p

Micozzi A. Madrid, ECCMID 2018

Empirical ceftazidime/avibactam for febrile neutropenia in 8 hematological patients colonized by CR-KPC KP

Optimitzaciótractament

empíric

Optimitzartractament

dirigit

DesescaladaDuradaPK/PD

Control focus

infecció

EscaladaDesescalada

Ceftolozane/tazobactam for MDRPA infections in patients with hematologic malignancies and HSCT recipients

Hakki M. Infection 2018

Disease NTP HSCT Infection Duration (days) Cure

1-ALL no no pneumonia 14 yes

2-AML yes no bacteremia 29 yes

3-MDS no yes pneumonia 31 no

4-ALL yes no bacteremia 17 no*

4* no no soft tissue 65 yes

5-AML yes no pneumonia 103 yes

6-AML yes yes bacteremia 15 yes

Fernández-Cruz A. Antimicrob Agents Chemother 2019

19 patients treated with C/T vs 39 controls treated with other antibiotics

Bacteremia in 10 patients (52.6%), and 5 with pneumonia (26%)

Combination with other ATB: 8 patients

Real-life experience with ceftolozane/tazobactam in patients with hematologic malignancy and P. aeruginosa infection: a case-control study

CEFTAZIDIME/AVIBACTAM versus other active agents for the treatment of bacteremia due to CRE in hematologic patients

Caston J. Int J Infect Dis 2017

• 8/31 (25.8%) patients with targeted ceftazidime/avibactam treatment, in combination with other antibiotics (2012-2016)

• 23 patients treated with “other antibiotics”

• Overall 30-day mortality and clinical cure (absence of signs and symptoms of infection within 14 days of therapy)

• Neutropenia 77.4%, endogenous source 45.2% (respiratory and CVC 19.4%),

• K. pneumoniae 86%, and OXA-48 61%

• Overall 30-day mortality 45.2%

Characteristics C/A Other pN =8 N = 23

Septic shock 3 (37.5) 10 (43.5) 1.00Empirical antibiotic

Carbapenem 7 (87.5) 20 (87) 1.00Aminoglycoside 4 (50) 8 (34.8) 0.67BLBLIs 1 (12.5) 2 (8.7) 1.00Tigecyclin 1 (12.5) 3 (13) 1.00Fosfomycin 1 (12.5) 1 (4.3) 0.45Colistin 1 (12.5) 1.(4.3) 0.45

Empirical antibioticAdequate 3 (37.5) 13 (56.5) 0.43Combination therapy 6 (75) 12 (52.2) 0.41

Targeted combination therapy 8 (100) 17 (94.4) 1.00Clinical cure 6 (85.7) 8 (34.8) 0.03Overall mortality 2 (25) 12 (52.2) 0.24

Caston J. Int J Infect Dis 2017

Infusional β-lactam antibiotics in febrile neutropenia: has the time come?

Variabilidad en los parámetros farmacocinéticos de los β-lactámicos en los pacientes con NF (cambios en el aclaramiento y el volumen de distribución)

En la NF se desconoce el % fT > MIC necesario. Puede conllevar a un tratamiento subóptimo y al desarrollo de resistencias

La infusión extendida o contínua de β-lactámicos mejora el fT > MIC en los pacientes graves o críticos

Poca experiencia en pacientes neutropénicos. Faltan estudios

prospectivos, controlados y randomizados

Abbott LJ. Curr Opin Infect Dis 2012

Optimitzaciótractament

empíric

Optimitzartractament

dirigit

DesescaladaDuradaPK/PD

Control focus

infecció

EscaladaDesescalada

Optimitzaciótractament

empíric

Optimitzartractament

dirigit

DesescaladaDuradaPK/PD

Control focus

infecció

EscaladaDesescalada

No totes les febres són infeccióEls quadres vírics no necessiten ATB

La profilaxi universal no es necessària

Pacient onco-hematològic

Si pacient estable i cultiusnegatius puc parar ATB malgrat neutropènia

No fa falta que canviï d’antibiòtic (carbapenem) a les 48h inici ATB si pacient estable i continua amb febre

Conclusions

• Tractament empíric inadequat augmenta mortalitat

• Conèixer colonització per MDR i establir tractament empíric útil BLEE i CRE

• P/T + amikacina pot ser útil d’entrada (meu hospital)

• Reduir MDR: ATB adequat, desescalar, no profilaxi universal, control focus, STOP ATB

• Nous fàrmacs eficaços en immunocompromesos

Treball

multidisciplinar

Nous reptes en l'era de les multi resistències: orientats al focusDisclosureIndexNúmero de diapositiva 4Número de diapositiva 5Número de diapositiva 6Risk factors for resistancesRisk factors for mortalityBacteremia due to ESBL-producing Enterobacteriaceae �in cancer patients Bacteremia due to MDR Pseudomonas aerugionsa in patients with hematological diseases Bacteremia due to carbapenem-resistant Enterobacteriaceae in patients with hematological diseases and HSCT recipientsIndexNúmero de diapositiva 13Número de diapositiva 14Número de diapositiva 15Inappropriate empirical antibiotic therapy in high-risk neutropenic patients with bacteremia Before choosing an empirical ATB therapy�take into account:Número de diapositiva 18Número de diapositiva 19Número de diapositiva 20Número de diapositiva 21Empirical antibiotic therapyNúmero de diapositiva 23Número de diapositiva 24Differences between neutropenic patients with hematological malignancies and solid tumors with BSINúmero de diapositiva 26Número de diapositiva 27Número de diapositiva 28Número de diapositiva 29Número de diapositiva 30Número de diapositiva 31Número de diapositiva 32Número de diapositiva 33Número de diapositiva 34Infusional β-lactam antibiotics in febrile neutropenia: has the time come?Número de diapositiva 36Número de diapositiva 37Número de diapositiva 38Número de diapositiva 39Número de diapositiva 40Número de diapositiva 41ConclusionsNúmero de diapositiva 43