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Benoît GUERYInfectious Diseases

CHRU Lille

Antibiotic strategies  How to treat

Multi-drug-resistant Pseudomonas

Wild Phenotype

Multi-drug-resistant Phenotype

Active Efflux

ImpermeabilityOther mechanisms :enzymatic inactivationTarget alteration ...

Multi-drug-resistant Pseudomonas

Fish 1995173 studies pooled

Resistance under treatment

Céph Péni Quin Ipm AGs AssTotal

E. coli 0 2.7 0 0 8 0.60.7

Proteus sp. 0 0.9 0 1.6 4 00.5

Klebsiella 3.2 6 2.8 1.4 1.5 <22.7

Enterobacter 10.1 10 4.1 4.1 26.1 2.46.8

Serratia 5.8 20 11.7 4 21.7 57.8

Acinetobacter 16.7 25 Nd Nd Nd NdNd

P. aeruginosa 10.6 14.4 15.5 34.7 13.4 14.315.4

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 2001Craig 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 2002

13999 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

Outcome No. of patients

Favorable therapeutic outcome 14/23

Unfavorable therapeutic outcome 9

Died while receiving therapy 7

Experienced relapsea 3

Survived

     Through end of therapy 16

     Through end of hospitalization 9

Linden et al, CID 2003Linden et al, CID 2003

5 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)LecA (PA-IL)

(Loris et al., 2003)(Loris et al., 2003)

LecB (PA-IIL)LecB (PA-IIL)

P. aeruginosa lectins

D-galactose L-fucose

Personal data

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

TTSS: a needle

Kubori et al. Science 1998

Shime et al, J Immunol 2001

Membrane disruption and toxin injection into cellMembrane disruption and toxin injection into cell

Cell Membrane

Pseudomonas aeruginosa

TTSSTTSS

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

ElastaseElastase

RhamnolipidRhamnolipidNot bactericidalNot bactericidalNot bacteriostaticNot bacteriostatic

QS Inhibition 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