Effect of clarithromycin on chronic respiratory infection caused by Pseudomonas aeruginosa with biofilm formation in an experimental murine model

Yanagihara, Katsunori; Tomono, Kazunori; Imamura, Yoshifumi; Kaneko, Yukihiro; Kuroki, Misuzu; Sawai, Toyomitsu; Miyazaki, Yoshitsugu; Hirakata, Yoichi; Mukae, Hiroshi; Kadota, Jun‐ichi; Kohno, Shigeru

doi:10.1093/jac/dkf013

Cited by 52 publications

(30 citation statements)

References 34 publications

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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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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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“…The purpose of the present study was to establish a safe dosing regimen for intravenously administered clarithromycin that achieves these levels in serum and to apply it to the management of experimental sepsis. Clarithromycin was administered alone or with amikacin for the treatment of acute pyelonephritis caused by multidrug-resistant P. aeruginosa; P. aeruginosa is a common nosocomial pathogen whose eradication is quite difficult (27). Antimicrobials were administered in parallel with bacterial challenge; clarithromycin was given as single dose or as two doses, with the second dose given after a short time interval, in an attempt to achieve steady-state levels in serum.…”

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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“…The mice were divided into 3 groups: control mice (no therapy), mice treated with 40 mg clarithromycin/kg of body weight twice a day (12,25), and mice treated with 100 mg/kg clarithromycin twice a day (39). The mice were treated for 3 days and then sacrificed 12 h after the final treatment.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Clarithromycin against Experimentally Induced Pneumonia Caused by Clarithromycin-Resistant Haemophilus influenzae in Mice

Nakamura¹,

Yanagihara

Araki

et al. 2010

Antimicrob Agents Chemother

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Clarithromycin is a 14-member lactone ring macrolide with potent activity against Haemophilus influenzae, including ampicillin-resistant strains. We evaluated the in vivo efficacy of clarithromycin at 40 mg/day and 100 mg/day for 3 days in the treatment of a murine model of pneumonia using a macrolide-resistant H. influenzae strain, which was also ampicillin resistant. The MIC of clarithromycin was 64 g/ml. The viable bacterial counts in infected tissues after treatment with 100 mg clarithromycin/kg of body weight were lower than the counts obtained in control and 40-mg/kg clarithromycin-treated mice. The concentrations of macrophage inflammatory protein 2 (MIP-2) and interleukin 1␤ (IL-1␤) in bronchoalveolar lavage fluid (BALF) samples from mice treated at both concentrations were lower than in the control group. Pathologically, following infection, clarithromycin-treated mice, particularly at a dose of 100 mg/kg, showed lower numbers of neutrophils in alveolar walls, and inflammatory changes had apparently improved, whereas large aggregates of inflammatory cells were observed within the alveoli of control mice. In addition, we demonstrated that clarithromycin has bacteriological effects against intracellular bacteria at levels below the MIC. Our results indicate that clarithromycin may be useful in vivo for macrolide-resistant H. influenzae, and this phenomenon may be related to the good penetration of clarithromycin into bronchoepithelial cells. We also believe that conventional drug susceptibility tests may not reflect the in vivo effects of clarithromycin.

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Effect of clarithromycin on chronic respiratory infection caused by Pseudomonas aeruginosa with biofilm formation in an experimental murine model

Cited by 52 publications

References 34 publications

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

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

Efficacy of Clarithromycin against Experimentally Induced Pneumonia Caused by Clarithromycin-Resistant Haemophilus influenzae in Mice

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