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
Host factors
Age
Factors related to infection
Neutropenia
Associated immunodepression
Site of infection
Cancer in progression
Clinical severity
Virulence factors related to pathogen
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
Chromosomic mutations
Cost fitness ?
-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
Is virulence-Resistance important for
Onco hematological patients ?
• Several antibiotic courses (ie, frequent selection)
• Primary bacteremia (ie, digestive translocation)
Antibiotic
Low proportion of resistant bacteria
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 ?
Community acquired
Hospital acquired
ICU acquired
Variable
alive
Deceased
p
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)
0,04
Adequate treatment
742 (78,4)
346 (71,2)
0,003
MDR-bacteria
75 (7,9)
62 (12,8)
0,0004
bacteremia
349 (36,9)
214 (43)
0,0002
Adequate treatment
176 (28,5)
126 (31,9)
0,18
MDR-bacteria
163 (26,4)
129 (32,7)
0,05
bacteremia
105 (17)
103 (26,1)
0,0001
Zahar et al, Crit Care Med 2011
Is mortality related to resistance ?
Univariate
MDR: alive 3,4%, Deceased 6%, p=0,04
Community acquired
n=1562
Inadequate Atb : alive 21% vs Deceased 29%
MDR: alive 7,9 % vs Deceased 12,8%, p=0,0004
Hospital acquired
n= 1432
ICU acquired
n=1012
Inadequate atb: alive 22% vs Deceased 29%
Multivariate*
SHR
SHR
1,7 (1,4-1,98), <0,0001
SHR
SHR
0,87 (0,54-1,4), 0,56
1,11 (0,82-1,52), 0,49
1,35 (1,12-1,92), <0,0001
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