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

Wild Phenotype

Multi-drug-resistant Phenotype

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

Fish studies pooled Resistance under treatment CéphPéniQuinIpmAGsAssTotal E. coli Proteus sp Klebsiella <22.7 Enterobacter Serratia Acinetobacter16.725NdNdNdNdNd P. aeruginosa

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

 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

Craig et al CID 2001

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

Obritsch et al, AAC 2004

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

Falagas et al, CID 2005

Outcome of colistin therapy for Pseudomonas aeruginosa infection OutcomeNo. of patients Favorable therapeutic outcome14/23 Unfavorable therapeutic outcome9 Died while receiving therapy7 Experienced relapse a a 3 Survived Through end of therapy16 Through end of hospitalization9 Linden et al, CID mg/kg/d

 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

Clin Microb Infect 2005  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

 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

 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

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

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

Cirioni et al, Crit Care Med 2007

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

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

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

Cirioni et al, AAC 2007 Tachyplesin III: antimicrobial peptid

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

Personal data

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

TTSS: a needle Kubori et al. Science 1998

Shime et al, J Immunol 2001

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

Le Berre et al, MMI 2006

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

Amk + clarithro Amk Clarithro Ctr BMC Inf Dis 2006

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