Infections with multidrug resistant bacteria in cancer patients: Impact on outcome? Pr Jean-Ralph Zahar Infection Control Unit AP-HP, Avicenne Hospital, Bobigny France Infection in immunocompromized patients: recent advances and future challenges Bekele Afessa Research Day, March 28th 2017, Paris Third meeting of the CarIng for CrItIcally Ill ImmunocompromIzed PatIents MultInatIonal Network – The Nine-I Network

The spread of MDR-GNB Spread of MDR-GNB in the hospital and the community Several risk factors : related to health care acquisition (community acquired?) More and more species with mechanisms of resistance (naturally vs acquired)

Main risks due to MDR spreading Confounding carriage with infection Missing infected patients with MDR-bacteria Use of broad spectrum antibiotics Reddy et al, Clin Inf Dis 2007 Goulenok et al, J Hosp Inf 2013 Razazi et al, Int Care Med 2012 Prinapori et al, Am J Infection 2012

Is there any clinical consequences related to resistance in ICU ? Prospective study (HELICS-ICU study) 119 699 patients, 537 ICU Moratlity, length of ICU stay Lambert et al, Lancet Inf Dis 2011

Several confounding factors Factors related to infection Site of infection Clinical severity Virulence factors related to pathogen Host factors Age Neutropenia Associated immunodepression Cancer in progression Factors related to treatment Treatment delay Complementary treatment Adequate antibiotic therapy

Vardakas et al, J Infection 2013

The threat of MDR-GNB infections in patients with hematologic malignancies Baker et al, Leuk and Lymphoma 2016

MDR-bacteria ? Acquired mechanism of resistance Genetic acquisition Cost fitness ? Genetic acquisition Chromosomic mutations -Compensatory mutation -Differences exist between mutation vs acquisition -Role of selective pressure

Is there any fitness cost ? Fitness cost is not the rule Compensatory mutation Different mechanisms of resistance # fitness cost (mutation vs HGT) Anderson et al, Nat Rev Microb 2010

Is virulence-Resistance important for Onco hematological patients ? Prolonged neutropenia and chemotherapy-induced mucositis MDR Gram-negative bacteria are increasingly encountered Increasing incidence of multi-drug resistant Gram-negative septicaemia during induction therapy of AML Murali et al, J Hosp Inf 2016 Baker et al, Leuk and Lymphoma 2016 Cornejo-Juárez et al, BMC Inf Dis 2016 render patients with hematologic malignancies highly vulnerable to Gram-negative bacteremia

Is virulence-Resistance important for Onco hematological patients ? Several antibiotic courses (ie, frequent selection) Primary bacteremia (ie, digestive translocation) Low proportion of resistant bacteria Antibiotic High proportion of resistant bacteria

Are virulence factors really needed ? Taur et al, Clin Inf Dis 2012

Is mortality related to resistance ? Evaluation of the respective influence of the causative pathogen and infection site on hospital mortality Prospective observational cohort data Subdistribution hazards model with corrections for competing risks and adjustment for potential confounders 4006 first episodes of severe sepsis Zahar et al, Crit Care Med 2011

Is mortality related to resistance ? Variable alive Deceased p Community acquired Adequate treatment 932 (79,1) 275 (71,6) 0,002 MDR-bacteria 40 (3,4) 23 (6) 0,04 bacteremia 475 (40,3) 186 (48,5) Hospital acquired 742 (78,4) 346 (71,2) 0,003 75 (7,9) 62 (12,8) 0,0004 349 (36,9) 214 (43) 0,0002 ICU acquired 176 (28,5) 126 (31,9) 0,18 163 (26,4) 129 (32,7) 0,05 105 (17) 103 (26,1) 0,0001 Zahar et al, Crit Care Med 2011

Is mortality related to resistance ? Univariate Multivariate* Community acquired n=1562 MDR: alive 3,4%, Deceased 6%, p=0,04 SHR 0,87 (0,54-1,4), 0,56 Inadequate Atb : alive 21% vs Deceased 29% SHR 1,7 (1,4-1,98), <0,0001 Hospital acquired n= 1432 MDR: alive 7,9 % vs Deceased 12,8%, p=0,0004 SHR 1,11 (0,82-1,52), 0,49 Inadequate atb: alive 22% vs Deceased 29% SHR 1,35 (1,12-1,92), <0,0001 ICU acquired n=1012 MDR: alive 26% vs Deceased 32%, p=0,05 SHR 0,98 (0,77-1,22), 0,9 Inadequate atb alive 46% vs Deceased 51% SHR 1,2 (1,05-1,75), 0,03 Modèle de Fine & Gray Ajusted on site infection, pathogens, severity, comorbidities Zahar et al, Crit Care Med 2011

Role of adequate antibiotic therapy sHR Intervalle de confiance p Community acquired 0,64 [0,51-0,8] 0,0001 Hospital acquired 0,72 [0,58 – 0,88] 0,0011 ICU acquired 0,79 [0,64 – 0,97] 0,0272 Zahar et al, Crit Care Med 2011

Marin et al, Medecine 2014

Patriarca et al, Biology Blood Marrow Transpl2016

1064 patients, 29% of them did not survive MDR P aeruginosa , ESBP-PE, Carbapenemase PE Zilberbeg et al, Crit Care Med 2014

How can we avoid mortality related to MDR bacteria ? Evoke the risk Choose the adequate antibiotic therapy Adapt dosage

Who is prone to be infected with MDR bacteria MDR-bacteria carriers MDR-bacteria carriers with high relative abundance Patients with risk factors ?

MDR-bacteria risk factors : ESBL example Risk factors shared with other MDR-GNB Bassetti, Curr Opin Infect Dis 2016

High carriage is associated with a higher risk of infection Ruppé et al, Antimicrob Agents Chemother 2013

Decrease of the absolute number of MDR-GNB ? Saidel-odes et al, Inf Control Hosp Epidemiol 2012

Adapt your antibiotic treatment ? Martinez et al, AAC 2010

Adapt your antibiotic treatment ? Legrand et al, Crit Care Med 2012

ICAAC 2012- K-1619 - Bacteremia Caused by Klebsiella pneumoniae Carbapenemase (KPC)-Producing Organisms: an Analysis of Attributable Mortality and Risk Factors for Recurrence – N. Girometti et al

To conclude Increase of MDR-Bacteria related infection Higher mortality related to inadequate antibiotic therapy We need To identify risk factors To anticipate the risk To adapt our antibiotic choices