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Antibiotic strategies  How to treat Multi-drug-resistant Pseudomonas

Antibiotic strategies  How to treat Multi-drug-resistant Pseudomonas. Benoît GUERY Infectious Diseases CHRU Lille . Wild Phenotype. Multi-drug-resistant Phenotype. Multi-drug-resistant Pseudomonas. Other mechanisms : enzymatic inactivation Target alteration . Impermeability.

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Antibiotic strategies  How to treat Multi-drug-resistant Pseudomonas

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  1. Antibiotic strategies  How to treat Multi-drug-resistant Pseudomonas Benoît GUERY Infectious Diseases CHRU Lille

  2. Wild Phenotype

  3. Multi-drug-resistant Phenotype

  4. Multi-drug-resistant Pseudomonas Other mechanisms : enzymatic inactivation Target alteration ... Impermeability Active Efflux

  5. Resistance under treatment Céph Péni Quin Ipm AGs Ass Total E. coli0 2.7 0 0 8 0.6 0.7 Proteus sp.0 0.9 0 1.6 4 0 0.5 Klebsiella3.2 6 2.8 1.4 1.5 <2 2.7 Enterobacter10.1 10 4.1 4.1 26.1 2.4 6.8 Serratia5.8 20 11.7 4 21.7 5 7.8 Acinetobacter16.7 25 Nd Nd Nd Nd Nd P. aeruginosa10.6 14.4 15.5 34.7 13.4 14.3 15.4 Fish 1995 173 studies pooled

  6. Multi-drug-resistant Pseudomonas • Risks factors for multi-drug-resistance • Treatment • Colistin • Other associations • Inhalation • The future?

  7. 17 multivariates /8 monovariates Prior use of antibiotics (15/17) Carbapenems (6) Fluoroquinolones (6) 3rdGC, then broad spectrum BL Mechanical Ventilation (5) ICU and Hospital stay (6) Comorbidities Falagas et al, J Hosp Inf 2006

  8. Craig et al CID 2001

  9. National surveillance of antimicrobial resistance in Pseudomonas aeruginosa isolates obtained from intensive care unit patients from 1993 to 2002 ceftazidime, ciprofloxacin, tobramycin, and imipenem 13999 strains Obritsch et al, AAC 2004

  10. Obritsch et al, AAC 2004

  11. Multi-drug-resistant Pseudomonas • Risks factors for multi-drug-resistance • Treatment • Colistin • Other associations • Inhalation • The future?

  12. Falagas et al, CID 2005

  13. 5 mg/kg/d Linden et al, CID 2003

  14. Prospective study • 185 patients infected with Acinetobacter baumannii and Pseudomonas aeruginosa • Hospitalisation> 48 h • 55 colistin group • 130 non colistin group • No difference for age, APACHE II score, comorbidities, and SOFA score Int Care Med 2005

  15. Retrospective study • 43 ICU patients • Multi-drug-resistant pathogens (P aeruginosa-A baumanii) • Clinical response: 74,4% • Renal function alteration 18,6% • Mortality 27,9% Colistine is an option Clin Microb Infect 2005

  16. Retrospective Cohort • 50 patients, Apache II: 16,1 • Mean daily dose: 4,5 MU for 21,3 days • Site of infection: Pneumonia (33%), bacteremia (27,8%), urine (11%), abdominal (11%) • Pathogen: A baumanii (51,9%), P aeruginosa (42,6%), K pneumoniae (3,7%) • Results • Clinical response: 66,7% • Nephrotoxicity: 8% Kasiakou et al, AAC 2005

  17. Prospective study • MDR P aeruginosa-A baumanii • 78 infections • Pulmonary 78,2% • Mean dosage: 5.5+/-1,1 MU/d during 9,3+/-3,8 days • Clinical response: 76,9% • Renal function alteration: 7 cases Int J AA 2006

  18. Multi-drug-resistant Pseudomonas • Risks factors for multi-drug-resistance • Treatment • Colistin • Other associations • Inhalation • The future?

  19. Multi-drug-resistant Pseudomonas • 7 isolates resistant to pip/merop/cefta/cefoperazone-sulb/aztreonam/amk/cipro • Bitherapy : • AZT+AMK : inhib 5/7 • Triple association • Cefta+Pip+Amk : inhib 7/7 • Cefta+Azt+Amk : inhib 7/7 Oie et al, JAC 2003

  20. Cirioni et al, Crit Care Med 2007

  21. Multi-drug-resistant Pseudomonas • Risks factors for multi-drug-resistance • Treatment • Colistin • Other associations • Inhalation • The future?

  22. 21 patients with MDR Pseudomonas • Nebulized polymyxin E • Clinical response 57,1% • Microbiological response 85,7% CID 2005

  23. Multi-drug-resistant Pseudomonas • Risks factors for multi-drug-resistance • Treatment • Colistin • Other associations • Inhalation • The future?

  24. Tachyplesin III: antimicrobial peptid Cirioni et al, AAC 2007

  25. LecA (PA-IL) LecB (PA-IIL) (Cioci et al., 2003) (Loris et al., 2003) P. aeruginosa lectins D-galactose L-fucose

  26. Personal data

  27. Personal data n = 10/groupe. * p < 0.05,** p < 0.01, *** p < 0.001 vs PAO1

  28. TTSS: a needle Kubori et al. Science 1998

  29. Shime et al, J Immunol 2001

  30. Cell Membrane Pseudomonas aeruginosa TTSS Membrane disruption and toxin injection into cell PcrV Protein Anti-PcrV Antibody (KB001)

  31. Le Berre et al, MMI 2006

  32. Tateda K et al. AAC 2001 QS Inhibition with macrolides Elastase Rhamnolipid Not bactericidal Not bacteriostatic QS Inhibition

  33. Amk + clarithro Amk Clarithro Ctr BMC Inf Dis 2006

  34. Conclusion • MDR is increasing • Colistin is an option • Multiple association can be tried even if the molecule alone is resistant • Inhaled antibiotics need to be further evaluated • From the pathophysiology, several specific molecules may be interesting

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