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Efficacy of colistin combination therapy in a mouse model caused by multi-drug resistant Pseudomonas aeruginosa. J Antimicrob Chemother

Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan.
Journal of Antimicrobial Chemotherapy (Impact Factor: 5.44). 02/2009; 63(3):534-42. DOI: 10.1093/jac/dkn530
Source: PubMed

ABSTRACT Multidrug-resistant Pseudomonas aeruginosa (MDRP) is becoming a serious problem in hospitals, especially in patients on ventilators. Recent data demonstrate that colistin may be effective for these patients, although limited in vitro and in vivo data are available. Our aim was to identify further characteristics of colistin for the therapy of pneumonia caused by MDRP.
The effects of colistin on clinical strains of MDRP were examined by susceptibility test, time-kill assay, lipopolysaccharide (LPS)-blocking assay and a mouse pneumonia model, alone or in combination with other antibiotics. For the pneumonia model, mice were intranasally infected with bacteria and kept in hyperoxic conditions to mimic ventilator-associated pneumonia.
As a single agent, colistin exhibited the strongest activity of the antimicrobial agents tested. In combination, maximum synergy was observed with colistin plus rifampicin. As expected, co-incubation of bacterial culture supernatants with colistin significantly reduced LPS activities with an associated decrease in cellular cytotoxicity. In the pneumonia model, intranasal, but not intravenous, colistin combined with rifampicin produced maximum survival protection. Pharmacokinetic analysis of colistin demonstrated the superiority of intranasal administration, judging from the compartmentalized high concentration and the long half-life in the lungs. Moreover, colistin therapy significantly decreased both production of inflammatory cytokines and LPS activity, even at a dose effecting no change in the bacterial burden in the lung.
These data strongly suggest that colistin may be an important option for combination therapy against critical MDRP infections. For pneumonia especially, intranasal colistin with rifampicin may be beneficial not only for synergistic antibacterial activity, but also for blocking LPS.

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    • "Polymyxin E, also known as colistin, is a cationic polypeptide antibiotic that interferes with the LPS and permeabilizes the outer membrane of Gramnegative bacteria. Clinical use for this antibiotic has been limited due to toxicity concerns, but at lower concentrations it has been used as adjuvant and enhances the activity of the antibiotics rifampin and vancomycin against Gram-negative pathogens (Aoki et al., 2009; Gordon et al., 2010). Molecules that prevent antibiotics from being pump out the bacterial cells are also desirable adjuvants. "
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    • "Polymyxin E, also known as colistin, is a cationic polypeptide antibiotic that interferes with the LPS and permeabilizes the outer membrane of Gramnegative bacteria. Clinical use for this antibiotic has been limited due to toxicity concerns, but at lower concentrations it has been used as adjuvant and enhances the activity of the antibiotics rifampin and vancomycin against Gram-negative pathogens (Aoki et al., 2009; Gordon et al., 2010). Molecules that prevent antibiotics from being pump out the bacterial cells are also desirable adjuvants. "
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    • "Similar results have been reported with a combination of high-dose tigecycline and colistin [40]. A synergistic combination of colistin with rifampin [41] and vancomycin [42] has been reported. Moreover, significant bactericidal activity was obtained in carbapenem-resistant K. pneumoniae, A. baumannii, P. aeruginosa, and E. coli isolates using combinations of polymyxin B, doripenem, and rifampin [43]. "
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