1. Multidrug-Resistant Bacteria in Solid Organ Transplantation Jordi Carratalà Department of Infectious Diseases IDIBELL-Hospital Universitari de Bellvitge

2. A 10-Year Study of Infection-Related Mortality in a Cohort Of 1218 Renal Transplant Recipients Linares L. Transpl Proc 2007

3. Bloodstream Infections Among Transplant Recipients Results of a Nationwide Surveillance in Spain Kidney Liver Heart Lung Pancreas Transplants (n) 1400 1012 291 167 65 Episodes (n) 121 134 32 17 17 Patients (n) 102 105 24 14 13 Incidence (%) 8.6 13.2 11 10.2 26.1 Moreno A. Am J Transpl 2007

4. Etiology of 321 Episodes of Bacteremia in SOT Recipients CNS 284 E. coli 127 A. baumanii 60 Pseudomonas spp 47 Enterococcus spp 46 Klebsiella spp 29 S. aureus 37 37% 17% 8% 6% 5% 4% Moreno A. Am J Transpl 2007 RESITRA

5. Bloodstream Infections Among SOT Recipients Proportion of Resistant Organisms (2003-2005) 14.5% 9.7% 16.2% Resistant Susceptible Enteric bacilliNo-fermentativeS. aureus Number of isolates Overall, 12% of isolates were MDR

6. MRSA Bacteremia in Liver Transplant Recipients Donskey CJ. NEJM 2009 Rochester, USA: 6.5% Lee SO. Liver Transpl 2011 Kyoto, Japan: 7.7% Lida T. Liver Transpl 2010 Clichy, France: 14% Bert F. Liver Transpl 2010 MRSA infection in SOT recipients has been associated with increased mortality (OR 9.0) Yamada K. Tohoku J Exp Med 2011

7. ESBL-Producing Escherichia coli E. coli CTX-M-9

8. Proportion of 3 rd Generation Cephalosporin Resistant Escherichia coli isolates 20012006

9. Proportion of 3 rd Generation Cephalosporin Resistant Escherichia coli isolates (2011) 10 to <25% 2011

10. Bacterial Urinary Tract Infection After SOT in the RESITRA Cohort Vidal E. Transplant Infect Dis 2012 Bacterial urinary tract infection, kidney transplant vs. others in the RESITRA cohort (4388 pts). 192 pts (4.4%) with 249 episodes of urinary infection (0.23 episodes/1000 transplant days). 156 pts were kidney or kidney/pancreas recipients. Escherichia coli (58%), 26% were ESBL-producing strains. Risk factors: age, female sex, and posttransplant dialysis.

11. A cohort observational study (2003-2006). 417 kidney transplant recipients (61 kidney/pancreas). Incidence of ESBL-producing and desrepressed AMpC ß-Lactamases was 11.8% (49 patients). The most frequent bacteria was E. coli (35/60) followed by Klebsiella spp (12/60). Risk Factors for Infection with Extended-Spectrum and AMpC ß-Lactamase-Producing Gram Negative Rods in Renal Transplantation Linares L. Am J Transpl 2008

12. Β-lactamase Mediated Resistance in GNB Isolates and Source of Infection Bacteremia: 10 episodes (17%)

13. Variable Adjusted OR 95% CI Kidney-Pancreas Tx3.5 1.6 – 7.8 Prior antibiotic use2.1 1.1 – 4.1 Posttransplant dialysis3.1 1.5 – 6.4 Posttransplant urinary5.8 2.2 – 14.9 obstruction Risk Factors for ESBL-Producing and Desrepressed AmpC β-lactamase GNB Infection in Kidney Recipients Linares L. Am J Transpl 2008

14. Extended-Spectrum β-Lactamase-Producing Bacterial Infections in Adult SOT Recipients Winters HA. Ann Pharmacother 2011 Retrospective case series of 20 cases of ESBL-producing bacterial infections (2003-2006). Median time to infection from Tx was 3.5 yrs (1-23 yrs) Overall, 85% of pts received inadequate empiric antibiotic therapy. 19 pts had clinical resolution; 1 patient died. 12 pts required readmission due to recurrence. Among 12 pts with recurrent infections, 75% received inadequate empiric antibiotic therapy

15. Klebsiella pneumoniae Infection in SOT Recipients Epidemiology and Antibiotic Resistance Linares L. Transplant Proc 2010 Prospective study of 1,057 SOT recipients (2003-2007). Of 116 episodes of KP infection, 62 (53%) were ESBL- producing strains (47 episodes <1month after TX). 34 pts (39%) had bacteremia; 15 due to resistant strains. None strain was KPC. The most frequent site of infection was urinary tract (72%). ESBL-producing strains were > frequent in KT recipients and in those requiring dialysis. There were 4 deaths and 3 were due to resistant strains.

16. Proportion of Klebsiella Pneumoniae Resistant Isolates (2011) 3 rd generation cephalosporins R Carbapenem R 10-<25% <1% ≥50%

17. Infection with KPC-producing Klebsiella pneumoniae in Solid Organ Transplantation Bergamasco MD. Transplant Infect Dis 2012 Outbreak of 12 cases of KPC-2 producing KP in Sao Paulo. Incidence: 26% KT (6); 17% HT (2); 13% LT (4). Median time to infection: 20 days. Site of infection: urinary tract (4), bacteremia (4), pneumonia (2), SSI (2). All but 1 patient had received prior antibiotic therapy (30 days). Treatment: Tige + PB (3); PB + carbapenem (3); PB (3); Tige + Imip (1) Overall 30-day mortality: 42%.

18. IDSA Report Boucher HW. Clin Infect Dis 2009

19. Vancomycin-resistant E. faecium Methicillin-resistant S. aureus (MRSA) ESBL-producing K. pneumoniae Carbapenem-resistant A. baumannii Carbapenem and quinolone-resistant P. aeruginosa Derepression chromosomic β-lactam and ESBL producing Enterobacter spp. Drug-resistant ESKAPE (rESKAPE)

20. 224 cases of bacteremia 127 (57%) ESKAPE bacteremia Non-rESKAPE 88 cases rESKAPE 39 cases (17.5%) Epidemiology, antibiotic therapy, and outcomes of bacteremia caused by rESKAPE in SOT Recipients Bodro M. ICAAC 2012Hospital de Bellvitge (Jan 2007- Mar 2012)

21. ESKAPE pathogens isolated in 224 bacteremias In SOT Recipients: Bellvitge Hospital (2007-2012) OrganismESKAPE total (n= 127) R-ESKAPE (n= 39) Enterococcus faecium70 Staphylococcus aureus144 Klebsiella pneumoniae297 Acinetobacter baumannii55 Pseudomonas aeruginosa2520 Enterobacter spp.83

22. Risk factors for rESKAPE bacteremia In SOT Recipients by Multivariate Analysis Variable OR 95% CI Prior transplantation 4.8 1.1 – 22.7 Nosocomial acquisition 4.0 1.3 – 12.2 Prior antibiotic therapy 3.0 1.1 – 9.7 Septic shock 3.5 1.5 – 8.3 Bodro M. ICAAC 2012

23. Antibiotic therapy and outcomes of SOT Recipients with rESKAPE Bacteremia Variable rESKAPE Other P n=54 n=185 Inadequate ATB therapy 43% 18% 0.003 ICU admission 48% 21% 0.001 Mechanical ventilation 33% 15% 0.001 Overall case-fatality rate (30d) 42% 15% 0.001 Bodro M. ICAAC 2012

24. Proportion of Carbapenems Resistant Pseudomonas aeruginosa Isolates (2011) 10-<25% 2011

25. Infections Caused by Pseudomonas aeruginosa in SOT Recipients 904 SOT recipients (Kidney, Liver, Pancreas) MDR Pseudomonas aeruginosa (≥ 3 ATBs) 110 episodes of infection (76 patients) Urinary tract infection: 42% Bacteremia: 30 episodes (27%) Incidence: - P. aeruginosa 8.4% - MDR P. aeruginosa 35% Mortality: - P. aeruginosa 4% - MDR P. aeruginosa 2.6% Linares L. SEIMC 2008

26. Severe Infection in a Lung Transplant Recipient Caused by Donor-Transmitted Carbapenem-R Acinetobacter baumanii Martins N. Transplant Infect Dis 2011 A 50-year-old female lung recipient with a proven donor transmission of carbapenem-R ABAU (Bla OXA-23 ) belonging to a new multilocus sequence type (ST231 )

27. Multidrug-Resistant Acinetobacter baumanii causing Necrotizing Fasciitis in a Pancreas-Kidney Transplant Recipient Clemente WT. Transplantation 2012

28. Heart RS. Curr Opin Infect Dis 2012

29. Empirical Treatment of Suspected Bacteremia in SOT Recipients Escalation strategy An uncomplicated presentation Without specific risk for resistant pathogens In centres where infections due to resistant pathogens are rare De-escalation strategy Pts with complicated presentations Individual risk factors for resistant pathogens Centres where resistant pathogens are frequent

30. Increasing prevalence of MDR bacteria in SOT recipients. Updated knowledge of local epidemiology and resistance patterns. No new drugs to treat infections due MDR organisms will be available. Selective effect of the increasing use of last resort ATBs of great concern. Need to improve preventive strategies and to optimize ATB therapy. Where are we going to?

31. La Pedrera, Gaudí, Barcelona Thank you for your attention!

32. Attributable Mortality Susceptible vs. Resistant Pathogens Organisms Attributable Mortality P Enteric bacilli cephalosporins-S 12 / 144 (8.3%) NS cephalosporins-R 2 / 24 (8.3%) Non-fermentative susceptible 8 / 83 (9.6%) 0.015 multidrug-resistant 4 / 9 (44%) S. aureus methicillin-S 2 / 31 (6.5%) NS methicillin-R 0 / 6 Moreno A. Am J Transpl 2007

33. Urinary Tract Infections in the Early Posttransplant Period After Kidney Transplantation Etiologic Agents and Their Suceptibility Kawecki D. Transpl Proc 2011 295 adults undergoing KTx between 2001-2007 (Poland) Prospective study of UTI first 4 w after Tx 291 bacterial isolates - Gram-negative bacilli 57% Serratia marcescens 32% Enterobacter cloacae 15% Escherichia coli 12% ESBL-producers 52% - Gram-positive organisms 36% HLAR enterococci 88% Vanco-R enterococci 11%