Combination therapy for chronic Pseudomonas aeruginosa respiratory infection associated with biofilm formation

Yanagihara, Katsunori; Tomono, Kazunori; Sawai, Toyomitsu; Kuroki, Misuzu; Kaneko, Yukihiro; Ohno, Hideaki; Higashiyama, Yasuhito; Miyazaki, Yoshitsugu; Hirakata, Yoichi; Maesaki, Shigefumi; Kadota, Jun‐ichi; Tashiro, Takayoshi; Kohno, Shigeru

doi:10.1093/jac/46.1.69

Cited by 39 publications

(34 citation statements)

References 14 publications

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“…NC, normal control. tokine production (42). In the present study, muc5ac glycoprotein was detected in lung samples 1 day after inoculation of the microorganism into the lung, and its concentration increased progressively from day 4 to day 14.…”

Section: Discussionsupporting

confidence: 58%

“…We and others have previously investigated the mechanisms of action and effectiveness of these agents in DPB (17,25,(40)(41)(42), as well as other airway inflammatory disorders, such as CF (10,16). Macrolides are considered to reduce mucus hypersecretion; Goswami et al (12) reported that erythromycin reduced glycoconjugate secretion in vitro, and Tamaoki and colleagues (31) reported that the same drug inhibited mucus viscosity by chloride channel inhibition.…”

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confidence: 99%

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Clarithromycin inhibits overproduction of muc5ac core protein in murine model of diffuse panbronchiolitis

Kaneko

Yanagihara²,

Seki³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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Long-term treatment of macrolide antibiotics is considered an effective treatment for diffuse panbronchiolitis (DPB). Although hypersecretion is a common feature of this disease, and it is known that macrolides inhibit mucin production, the mechanism of the effect on mucin production is unclear. The aim of our study was to determine the production of muc5ac core protein, a major core protein of mucin in airway secretion, and the effect of clarithromycin treatment on such production in a mouse model mimicking DPB. Alcian blue-periodic acid-Schiff-positive cells were detected in the lungs of Pseudomonas aeruginosa-infected mice. Western blots of these mice showed muc5ac glycoprotein at day 1 and increased progressively from day 4 to day 14 after inoculation of bacteria. Clarithromycin (10 mg · kg-1 · day-1 for 7 days) significantly reduced the muc5ac expression at both the mRNA and protein levels. To investigate the role of molecules upstream in muc5ac regulation, we examined the role of mitogen-activated protein kinase. Extracellular signal-regulated kinase 1/2 phosphorylation increased in the infected lung and decreased after treatment. Our results suggest that overproduction of muc5ac plays an important role in the pathogenesis of DPB and that clinical improvement following macrolide therapy seems to involve, at least in part, its inhibition of mucin overproduction, through modulation of intracellular signal transduction.

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Section: Discussionsupporting

confidence: 58%

mentioning

confidence: 99%

Clarithromycin inhibits overproduction of muc5ac core protein in murine model of diffuse panbronchiolitis

Kaneko

Yanagihara²,

Seki³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…These infections often occur in the lungs of individuals with the heritable disease CF (19) and the peritoneum of individuals undergoing CAPD (25). Although a number of in vivo models exist to study P. aeruginosa lung and peritoneal pathogenesis (14,29,(43)(44)(45), most of these models do not possess the versatility to perform genome-scale gene expression studies and study multispecies consortia. To begin to understand in vivo gene expression, we grew P. aeruginosa in a dialysis membrane chamber (DMC) implanted into the peritoneal cavity of a rat (1).…”

Section: Resultsmentioning

confidence: 99%

Staphylococcus aureus Serves as an Iron Source for Pseudomonas aeruginosa during In Vivo Coculture

et al. 2005

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Pseudomonas aeruginosa is a gram-negative opportunistic human pathogen often infecting the lungs of individuals with the heritable disease cystic fibrosis and the peritoneum of individuals undergoing continuous ambulatory peritoneal dialysis. Often these infections are not caused by colonization with P. aeruginosa alone but instead by a consortium of pathogenic bacteria. Little is known about growth and persistence of P. aeruginosa in vivo, and less is known about the impact of coinfecting bacteria on P. aeruginosa pathogenesis and physiology. In this study, a rat dialysis membrane peritoneal model was used to evaluate the in vivo transcriptome of P. aeruginosa in monoculture and in coculture with Staphylococcus aureus. Monoculture results indicate that approximately 5% of all P. aeruginosa genes are differentially regulated during growth in vivo compared to in vitro controls. Included in this analysis are genes important for iron acquisition and growth in low-oxygen environments. The presence of S. aureus caused decreased transcription of P. aeruginosa ironregulated genes during in vivo coculture, indicating that the presence of S. aureus increases usable iron for P. aeruginosa in this environment. We propose a model where P. aeruginosa lyses S. aureus and uses released iron for growth in low-iron environments.Pseudomonas aeruginosa is a gram-negative opportunistic human pathogen commonly found in water and soil. P. aeruginosa causes a number of chronic and acute infections and is noted for its inherent resistance to many clinically relevant antibiotics. Two of the most common infections caused by P. aeruginosa are chronic colonization of the lungs of individuals with the genetic disease cystic fibrosis (CF) (19) and peritonitis in individuals undergoing continuous ambulatory peritoneal dialysis (CAPD) (25). The lungs of CF patients are commonly colonized before the age of 8, and most individuals maintain these infections throughout their lifetimes. High infection rates are also associated with CAPD, which is often used to treat end-stage renal disease.P. aeruginosa physiology and gene expression during in vivo growth is largely unknown. Using in vivo expression technology (IVET), Wang et al. identified 19 P. aeruginosa genes inducible during growth in a neutropenic mouse (40). Although that study identified several new genes important for virulence in P. aeruginosa, it did not provide a comprehensive analysis of in vivo gene expression. Two recent studies using Pasteurella multocida and Borrelia burgdorferi have provided a more comprehensive view of in vivo bacterial gene expression by using DNA microarrays (3, 4, 33). These studies illustrate that a significant number of genes (2 to 8% of all the genes in the genomes) are differentially regulated in vivo, suggesting that the in vivo environment is distinct from normal in vitro culture conditions.Although evaluation of the transcriptomes of in vivo-grown bacteria provides a snapshot of transcription under monoculture growth conditions, it is clear that many in...

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“…Clarithromycin may alter the rate of protein synthesis and the subsequent production of virulence factors by these isolates (12,22), and it may act in synergy both in vitro and in vivo with antipseudomonal agents to decrease their growth (3,28). The hypothesis that the synergy of clarithromycin and amikacin against multidrug-resistant P. aeruginosa explains the prolonged survival of the animals in the present study is not likely for three reasons: (i) the MIC of clarithromycin was significantly higher than the levels achieved in serum (Table 1); (ii) time-kill assays performed with concentrations of clarithromycin and amikacin equal to those in serum failed to disclose any additive or synergistic interaction (Fig.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory Clarithromycin Treatment of Experimental Sepsis and Acute Pyelonephritis Caused by Multidrug-Resistant Pseudomonas aeruginosa

Giamarellos‐Bourboulis¹,

Adamis

Laoutaris³

et al. 2004

Antimicrob Agents Chemother

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Clarithromycin was administered intravenously to 55 rabbits to evaluate its effect on experimental sepsis caused by multidrug-resistant Pseudomonas aeruginosa. Acute pyelonephritis was induced after ligation of the right ureter and injection of 10 8 CFU of the test isolate per kg of body weight into the renal pelvis. The animals were divided into six groups: group A, controls; group B, rabbits that received one intravenous dose of 80 mg of clarithromycin per kg concomitantly with bacterial challenge; group C, rabbits that received two doses of clarithromycin, the second one of which was given 2 h after the first one; group D, rabbits that received 15 mg of amikacin per kg; group E, rabbits that received one dose of clarithromycin and amikacin; and group F, rabbits that received two doses of clarithromycin and amikacin. Serum endotoxin levels were estimated by the QCL-1000 Limulus amoebocyte lysate assay, tumor necrosis factor alpha (TNF-␣) levels were measured by a bioassay, and malondialdehyde (MDA) levels were measured by the thiobarbiturate assay. Viable bacterial counts in various tissue samples were also assessed. The mean survival times of the animals in groups A, B, C, D, E, and F were 4.50, 7.69, 4.07, 4.55, 11.55, and 11.60 days, respectively (P ‫؍‬ 0.033 for group D versus group F, P ‫؍‬ 0.006 for group D versus group E, P ‫؍‬ not significant for group B versus group E, P ‫؍‬ 0.042 for group C versus group F). Serum endotoxin levels were similar between groups at all sampling times; TNF-␣ and MDA levels in groups B, C, E, and F decreased significantly over follow-up. The numbers of viable bacterial cells in the infected kidney were similar among the groups; those in the liver, spleen, lungs, and mesenteral lymph nodes were significantly decreased in groups B, E, and F compared to those in groups A and D. It is concluded that a prolongation of survival in animals with experimental sepsis caused by multidrug-resistant P. aeruginosa was achieved after coadministration of clarithromycin and amikacin and that the increased survival was probably attributable to the immunomodulatory properties of clarithromycin.Clarithromycin is a macrolide classically known to possess an antimicrobial spectrum that includes gram-positive cocci and atypical pathogens (23). However, an increasing body of evidence suggests that clarithromycin possesses considerable antiinflammatory and immunomodulatory properties, recommending its administration for the treatment of chronic inflammatory conditions like diffuse panbronchiolitis and cystic fibrosis (11,21,26). Its immunomodulatory properties are observed in vitro at concentrations close to 10 g/ml (14). On the basis of that finding, intravenous administration of clarithromycin leading to the same levels in blood might be beneficial for the treatment of an acute inflammatory state like sepsis.Pseudomonas aeruginosa is a common pathogen that is involved in nosocomial sepsis and that is often characterized nowadays by multidrug resistance (18). In the present study, intravenous clar...

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Combination therapy for chronic Pseudomonas aeruginosa respiratory infection associated with biofilm formation

Cited by 39 publications

References 14 publications

Clarithromycin inhibits overproduction of muc5ac core protein in murine model of diffuse panbronchiolitis

Clarithromycin inhibits overproduction of muc5ac core protein in murine model of diffuse panbronchiolitis

Staphylococcus aureus Serves as an Iron Source for Pseudomonas aeruginosa during In Vivo Coculture

Immunomodulatory Clarithromycin Treatment of Experimental Sepsis and Acute Pyelonephritis Caused by Multidrug-Resistant Pseudomonas aeruginosa

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