Effects of sub-MICs of erythromycin and other macrolide antibiotics on serum sensitivity of Pseudomonas aeruginosa

Tateda, Kazuhiro; Hirakata, Yoichi; Furuya, Nobuhiko; Ohno, Akira; Yamaguchi, Keizo

doi:10.1128/aac.37.4.675

Cited by 40 publications

(27 citation statements)

References 27 publications

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“…On the other hand, it has been shown that drug exposure to infected tissue in critically ill patients or patients with arterial occlusive disease might as well be significantly decreased by infection or otherwise triggered hemodynamic alterations (51)(52)(53). In addition, there is evidence demonstrating that subinhibitory macrolide concentrations do still have an impact on a variety of bacterial virulence factors, including adhesion ability to epithelial cells, toxin production, and susceptibility to the host's immune defense (54)(55)(56)(57). Also, macrolide antibiotics have been shown to possess beneficial anti-inflammatory and immunomodulatory properties which might be active even at concentrations below the MIC (58,59).…”

Section: Discussionmentioning

confidence: 99%

Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy

Matzneller

Krasniqi

Kinzig

et al. 2013

Antimicrob Agents Chemother

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cAlthough azithromycin is extensively used in the treatment of respiratory tract infections as well as skin and skin-related infections, pharmacokinetics of azithromycin in extracellular space fluid of soft tissues, i.e., one of its therapeutic target sites, are not yet fully elucidated. In this study, azithromycin concentration-time profiles in extracellular space of muscle and subcutaneous adipose tissue, but also in plasma and white blood cells, were determined at days 1 and 3 of treatment as well as 2 and 7 days after the end of treatment. Of all compartments, azithromycin concentrations were highest in white blood cells, attesting for intracellular accumulation. However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Calculation of the area under the concentration-time curve from 0 to 24 h (AUC 0 -24 )/MIC 90 ratios for selected pathogens suggests that azithromycin concentrations measured in the present study are subinhibitory at all time points in both soft tissues and at the large majority of observed time points in plasma. Hence, it might be speculated that azithromycin's clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects, including immunomodulation and influence on bacterial virulence factors. However, prolonged subinhibitory azithromycin concentrations at the target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern. In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance.

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Section: Discussionmentioning

confidence: 99%

Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy

Matzneller

Krasniqi

Kinzig

et al. 2013

Antimicrob Agents Chemother

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“…Although Pseudomonas aeruginosa is generally highly resistant to macrolides, erythromycin (ERY) suppressed the production of exotoxin A and proteases by this organism at concentrations well below the MIC (6). It was also demonstrated that sub-MICs of macrolide antibiotics decreased protein synthesis (18), enhanced the sensitivity of P. aeruginosa in serum (17), and suppressed biofilm formation through inhibition of alginic acid (7). Based on these reports, certain macrolides at sub-MICs were expected to have clinical effects on patients with respiratory infections caused by gram-negative rods such as P. aeruginosa, and in fact long-term low-dose administration of ERY produced clinical improvement in patients with diffuse pulmonary panbronchiolitis associated with P. aeruginosa infection (16).…”

mentioning

confidence: 99%

Effect of Subinhibitory Concentrations of Macrolides on Expression of Flagellin inPseudomonas aeruginosaandProteus mirabilis

Kawamura-Sato

Iinuma

Hasegawa³

et al. 2000

Antimicrob Agents Chemother

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In the present study we showed by molecular analysis that the inhibition of motility by macrolides in Proteus mirabilis and Pseudomonas aeruginosa was well correlated with the loss of the expression of flagellin. Erythromycin, clarithromycin, and azithromycin at subinhibitory concentrations (sub-MICs) suppressed the expression of flagellin dose dependently. Azithromycin had the strongest inhibitory effect on the expression of P. aeruginosa flagellin, whereas 16-membered rokitamycin had only a weak inhibitory effect. These results indicate the potential effectiveness of sub-MICs of erythromycin, clarithromycin, and azithromycin for the treatment of patients with P. mirabilis and P. aeruginosa infections.Macrolide antibiotics have been widely used to treat various infections. They bind to the 50S ribosomal subunit, resulting in blockage of transpeptidation and/or translocation. The antimicrobial activity of macrolides is broad in spectrum, being exhibited against gram-positive and some gram-negative bacteria, such as Neisseria spp., Campylobacter spp., Haemophilus spp., and Legionella spp. (4). In contrast, most species of Enterobacteriaceae and nonglucose-fermenting gram-negative rods such as Pseudomonas spp. are innately resistant to macrolides (15).Some reports have demonstrated that the treatment of bacteria with subinhibitory concentrations (sub-MICs) of macrolide antibiotics suppressed the expression of bacterial virulence factors in various gram-negative rods (5, 8). Although Pseudomonas aeruginosa is generally highly resistant to macrolides, erythromycin (ERY) suppressed the production of exotoxin A and proteases by this organism at concentrations well below the MIC (6). It was also demonstrated that sub-MICs of macrolide antibiotics decreased protein synthesis (18), enhanced the sensitivity of P. aeruginosa in serum (17), and suppressed biofilm formation through inhibition of alginic acid (7). Based on these reports, certain macrolides at sub-MICs were expected to have clinical effects on patients with respiratory infections caused by gram-negative rods such as P. aeruginosa, and in fact long-term low-dose administration of ERY produced clinical improvement in patients with diffuse pulmonary panbronchiolitis associated with P. aeruginosa infection (16).The present study was therefore undertaken to clarify the in vitro effectiveness of sub-MICs of macrolides as assessed by the inhibition of flagellin expression in P. aeruginosa and Proteus mirabilis. Flagella are among the virulence factors of gramnegative rods and have a role in the initiation of biofilm formation (14). Early studies showed that exposure to sub-MICs of the macrolide azithromycin (AZM) resulted in loss of motility due to the absence of flagella in P. mirabilis and P. aeruginosa (10, 11). However, these observations were based on the conventional light-microscopic examinations and therefore were not quantitative. We describe here the results of molecular analysis of the flagellin inhibition by sub-MICs of macrolides.Nonmucoid P. aeruginosa ...

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“…This combination is often used against Pseudomonas species in clinical practice (Kim et al, 2001). Treatment with subinhibitory concentrations (sub-MIC) of some antibiotics may influence bacterial virulence parameters (Wolter & McCormack, 1998), such as adherence (Wilson & Schurr, 2002;Wolter & McCormack, 1998;Trafny et al, 1995), cellsurface hydrophobicity (CSH) (Tateda et al, 1993), biofilm formation (Drago et al, 2001;Kim et al, 2001;Sonstein & Burnham, 1993), sensitivity to oxidative stress (Hassett et al, 1999) and motility (Braga et al, 2000;Drago et al, 2001). …”

Section: Introductionmentioning

confidence: 99%

Effect of subinhibitory concentration of piperacillin/tazobactam on Pseudomonas aeruginosa

Fonseca

Extremina

Sousa

2004

Journal of Medical Microbiology

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Subinhibitory concentrations (sub-MICs) of antibiotics, although not able to kill bacteria, can modify their physico-chemical characteristics and the architecture of their outermost surface and may interfere with some bacterial functions. This study investigated the ability of sub-MIC piperacillin/ tazobactam (P/T) to interfere with the bacterial virulence parameters of adhesiveness, cell-surface hydrophobicity, motility, biofilm formation and sensitivity to oxidative stress. Antimicrobial activity against five Pseudomonas aeruginosa clinical isolates, representative of clonal lineages of 96 strains of nosocomial origin, and six control strains (ATCC 27853, PAO1, AK1, MT1562, PT623, PAO1algC) was evaluated in vitro using the NCCLS microdilution method. The effects of sub-MIC on bacterial adhesion and biofilm formation were studied using a modified microtitre plate assay. The relative cell-surface hydrophobicity of P. aeruginosa strains was determined by measuring their ability to adhere to n-hexadecane. P. aeruginosa that had been exposed overnight to P/T and incubated with P/T in the plate were also screened for their ability to swim using flagella and to twitch and for their sensitivity to oxidative stress. The results obtained showed that the impact of sub-MIC P/T on bacterial characteristics was different for the various strains of P. aeruginosa. There was a change in bacterial morphology and hydrophobicity that could explain a significant decrease in adhesion values in all clinical isolates and controls tested, a decrease in biofilm formation, a significant increase in sensitivity to oxidative stress, a significant decrease in flagellum-mediated swimming and a decrease in type IV fimbriae-mediated twitching. The results obtained indicate that sub-MIC P/T interferes with the pathogenic potential of P. aeruginosa.

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Effects of sub-MICs of erythromycin and other macrolide antibiotics on serum sensitivity of Pseudomonas aeruginosa

Abstract: We examined the effects of sub-MICs of erythromycin (EM) and other macrolide antibiotics on the serum sensitivity ofPseudomonas aeruginosa. P. ae_wginasa S-6

Cited by 40 publications

References 27 publications

Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy

Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy

Effect of Subinhibitory Concentrations of Macrolides on Expression of Flagellin inPseudomonas aeruginosaandProteus mirabilis

Effect of subinhibitory concentration of piperacillin/tazobactam on Pseudomonas aeruginosa

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