Efficacy of colistin combination therapy in a mouse model of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa

Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan.
Journal of Antimicrobial Chemotherapy (Impact Factor: 5.34). 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: This article discusses ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Ventilator-associated pneumonia caused by P. aeruginosa is one of the leading causes of morbidity and mortality in the intensive care unit, and nowadays it represents a major concern due to the increasing resistance rate of the pathogen to different classes of antibiotics. Here, the choice between a combination therapy and a monotherapy in the empirical setting is analyzed and discussed, by focusing on the recommendations of different published guidelines. Pros and cons of the different possible associations are analyzed and suggestions are given in light of the emergence of multidrug-resistant strains. Route of administration is also discussed, with an emphasis on the use of nebulized antibiotics. Optimal duration of treatment is an additional point of discussion, and explanations are provided for the suggested longer course compared with that of other etiologies.
    Future Microbiology 04/2014; 9:465-74. DOI:10.2217/fmb.14.7 · 4.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Combination antibiotic therapy for Gram-negative sepsis is controversial. The present review provides a brief summary of the existing knowledge on combination therapy for severe infections with multidrug-resistant Pseudomonas spp., Acinetobacter spp., and Enterobacteriaceae. Empirical combination antibiotic therapy is recommended for severe sepsis and septic shock to reduce mortality related to inappropriate antibiotic treatment. Because definitive combination therapy has not been proven superior to monotherapy in meta-analyses, it is generally advised to de-escalate antibiotic therapy when the antibiotic susceptibility profile is known, although it cannot be excluded that some subgroups of patients might still benefit from continued combination therapy. Definitive combination therapy is recommended for carbapenemase-producing Enterobacteriaceae and should also be considered for severe infections with Pseudomonas and Acinetobacter spp. when beta-lactams cannot be used. Because resistance to broad-spectrum beta-lactams is increasing in Gram-negative bacteria and because no new antibiotics are expected to become available in the near future, the antibacterial potential of combination therapy should be further explored. In vitro data suggest that combinations can be effective even if the bacteria are resistant to the individual antibiotics, although existing evidence is insufficient to support the choice of combinations and explain the synergistic effects observed. In vitro models can be used to screen for effective combinations that can later be validated in animal or clinical studies. Further, in the absence of clinical evidence, in vitro data might be useful in supporting therapeutic decisions for severe infections with multidrug-resistant Gram-negative bacteria.
    Upsala journal of medical sciences 03/2014; 119(2). DOI:10.3109/03009734.2014.899279 · 0.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The purposes of this study were to establish a rabbit multidrug-resistant Pseudomonas aeruginosa (MDRP) keratitis model, and test the efficacy of levofloxacin, colistin methanesulfate (CL-M), colistin sulfate (CL-S) and polymyxin B (PL-B) against MDRP infection. In a rabbit eye, making a 2-mm circular corneal excision, and MDRP strain #601 or representative P. aeruginosa strain IID1210 were instilled into the corneal concavity. IID1210 was used to confirm this model developed P. aeruginosa keratitis. After MDRP keratitis developed, we treated the eyes with levofloxacin, CL-M, CL-S or PL-B eye drops. The infected eyes were evaluated by clinical score, histopathological examination and viable bacterial count (CFU). Rabbits developed MDRP keratitis reproducibly after instilled the bacteria into the corneal lesion. MDRP produced severe keratitis similarly with IID1210, as shown by slit lamp examination and clinical score. In MDRP keratitis models, clinical scores and viable bacterial counts were significantly lower in levofloxacin- and CL-M-treated groups compared with PBS-treated group, but the magnitudes of reduction were not remarkable. However, clinical scores were dramatically lowered in CL-S- and PL-B-treated groups compared with PBS-treated group. CL-S- and PL-B-treated group were kept corneal translucency and little influx of polymorphonuclear neutrophils in histopathological examination. In addition, both CL-S- and PL-B-treated groups were not detected viable bacteria in infected cornea. Using our MDRP keratitis model, we showed that topical levofloxacin and CL-M are not adequately effective, while CL-S and PL-B are efficacious in controlling MDRP keratitis. Especially, PL-B, which is commercially available eye drop, might be most effective against MDRP.
    Journal of Infection and Chemotherapy 12/2013; 20(5-6). DOI:10.1016/j.jiac.2013.10.015 · 1.38 Impact Factor