1. 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

2. 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)

3. 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

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

5. 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

6. Vardakas et al, J Infection 2013

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

8. 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

9. 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

10. 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

11. 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

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

13. 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

14. 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

15. 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

16. 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

17. Marin et al, Medecine 2014

18. Patriarca et al, Biology Blood Marrow Transpl2016

19. 1064 patients, 29% of them did not survive
MDR P aeruginosa , ESBP-PE, Carbapenemase PE
Zilberbeg et al, Crit Care Med 2014

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

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

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

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

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

25. Adapt your antibiotic treatment ?
Martinez et al, AAC 2010

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

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

28. 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