Influence of Macrolide Susceptibility on Efficacies of Clarithromycin and Azithromycin against
            <i>Streptococcus pneumoniae</i>
            in a Murine Lung Infection Model

Hoffman, Holly; Klepser, Michael E.; Ernst, Erika J.; Petzold, Chris; Sa'adah, Loai Mohammed; Doern, Gary V.

doi:10.1128/aac.47.2.739-746.2003

Cited by 32 publications

(25 citation statements)

References 19 publications

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“…However, there are few studies about the clinical outcome of pneumonia caused by erm B-mediated high-level MRSP. HOFFMAN et al [25] reported that CLR and AZM did not improve the survival rates. In contrast, in the present immunocompetent mouse model, CLR and AZM were effective even against high-level MRSP.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, the doses of CLR and AZM were chosen to achieve target parameters similar to those observed in healthy humans [25]. Nevertheless, neither CLR nor AZM reduced the viable number of pneumococci lower than control in murine lungs.…”

Section: Discussionmentioning

confidence: 99%

“…Antibiotics were administered through oral gavage. The survival rates were determined daily over a 10-day post-infection period [25].…”

Section: Laboratory Animalsmentioning

confidence: 99%

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Effects of macrolides on pneumolysin of macrolide-resistantStreptococcus pneumoniae

Fukuda¹,

Yanagihara²,

Higashiyama³

et al. 2006

Eur Respir J

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To clarify the discrepancy between increasing resistance and conservative clinical effects of macrolides on macrolide-resistant Streptococcus pneumoniae, the authors evaluated the effects of sub-minimum inhibitory concentrations of macrolides on pneumolysin.In vitro, S. pneumoniae was incubated with 1, 2 and 4 mg?mL -1 of clarithromycin (CLR) and azithromycin (AZM) for 8 h. Western blot analysis and haemolytic assay were performed to examine the production and activities of pneumolysin. In vivo, mice were infected with S. pneumoniae intra-nasally and treated with CLR (40 or 200 mg?kg -1 twice daily) or AZM (40 or 200 mg?kg -1 once daily) orally for 7 days. After 72 h post-infection, western blot analysis was performed to examine pneumolysin production in lungs. Survival rates were observed for 10 days.In vitro, every concentration of macrolide inhibited pneumolysin production more than the control. CLR (2 and 4 mg?mL ) improved the survival rates more than the control.The study results show that sub-minimum inhibitory concentrations of macrolides reduced pneumolysin. This might be related to the effectiveness of macrolides against pneumonia caused by high-level macrolide-resistant Streptococcus pneumoniae. Further investigations are necessary to evaluate the effects of macrolides on macrolide-resistant Streptococcus pneumoniae.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of macrolides on pneumolysin of macrolide-resistantStreptococcus pneumoniae

Fukuda¹,

Yanagihara²,

Higashiyama³

et al. 2006

Eur Respir J

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“…Nevertheless, none of the macrolides tested in this study were able to protect mice from bloodstream invasion by macrolide-resistant S. pneumoniae, which resulted in the death of all infected mice. In neutropenic mice, however, the efficacy of CLR and AZM against clinical isolates of macrolide-resistant S. pneumoniae varied with the level of macrolide resistance of the pathogen (20), which indicates that the enhancement of local resistance against macrolideresistant S. pneumoniae by sub-MIC levels of macrolide compounds may require an immunocompetent status of the hosts. Furthermore, this fact strongly suggests that the direct antimicrobial activity of macrolides should be necessary for complete protection against a high level of macrolide-resistant S. pneumoniae, regardless of the degree of innate immunity in the hosts.…”

Section: Vol 51 2007 Macrolides and Resistant S Pneumoniae 1749mentioning

confidence: 98%

Roxithromycin Favorably Modifies the Initial Phase of Resistance against Infection with Macrolide-Resistant Streptococcus pneumoniae in a Murine Pneumonia Model

Yasuda

Kasahara

Mizuno³

et al. 2007

Antimicrob Agents Chemother

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Sub-MIC levels of macrolides down-regulate bacterial virulence factors and suppress inflammatory processes. The ability of macrolides to reduce the production of pneumolysin has been shown to explain the discrepancy between in vitro resistance and outcomes with macrolides against macrolide-resistant Streptococcus pneumoniae. In this study, we determined whether the ability of macrolides to regulate inflammatory processes is beneficial for innate resistance to macrolide-resistant pneumococci in a murine pneumonia model. Among the macrolides tested, only roxithromycin did not affect in vitro pneumococcal virulence factors at sub-MIC levels. Roxithromycin (1.25 to 10 mg/kg of body weight/day) was administered to mice by oral gavage for 3 days before infection with a resistant strain of S. pneumoniae. We evaluated the efficacy of the treatment by determining mouse survival curves and by measuring bacterial burdens and several inflammatory parameters in the airways. Pneumolysin and PspA in infected lungs were examined by Western blot assay. Roxithromycin at doses of >5 mg/kg/day increased the median survival time and retarded bacteremia without suppressing the production of pneumolysin and PspA in infected lungs. This treatment reduced matrix metalloproteinase-7 expression and activation and keratinocyte-derived chemokine production in the lungs, while it increased mononuclear cell responses in the lungs, with enhanced bacterial clearance. Concentrations of roxithromycin in plasma and tissues were below the MICs for the inoculated strain during infection. The treatment also reduced inflammatory responses to killed pneumococci in the lungs. These results suggest that the modification by roxithromycin of airway inflammatory responses, including those of matrix metalloproteinase-7 and phagocytes, is beneficial for initial resistance to macrolide-resistant pneumococci.Streptococcus pneumoniae is the most prevalent pathogen associated with community-acquired pneumonia, and the emergence of antibiotic resistance among pneumococcal isolates linked to community-acquired pneumonia has been of great concern. Especially, the incidence of macrolide-resistant S. pneumoniae is rapidly increasing (11,22). Nevertheless, macrolide compounds have been empirically among the firstline drugs for the treatment of outpatients with communityacquired pneumonia. Such empirical therapy is likely to involve the risk of exacerbating the disease in cases of infection with macrolide-resistant S. pneumoniae (31, 32). However, despite the appreciable level of macrolide resistance, concordance between in vitro macrolide susceptibility and clinical outcomes among patients with community-acquired pneumonia is lacking (5, 34); the exact clinical relevance of in vitro findings has yet to be determined. A recent report (12) has shown that the ability of macrolides to reduce pneumococcal virulence factors may account for the discordance between the in vitro resistance of pneumococci and the conservative clinical effects of macrolides. In addition to the su...

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“…Because intracellular concentrations of macrolide antibiotic often exceed the MIC of phagocytized pathogens, macrolides have also been demonstrated to be effective against microorganisms with in vitro macrolide resistance [35,36]. The excellent intracellular penetration of macrolides also appears to explain their effectiveness against intracellular pathogens [34].…”

Section: Effects On Host-pathogen Interactionsmentioning

confidence: 99%

Immunomodulatory Effects of Macrolide Antibiotics – Part 1: Biological Mechanisms

et al. 2010

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Macrolide antibiotics are well known for their antibacterial and anti-inflammatory properties. This article provides an overview of the biological mechanisms through which macrolides exert this ‘double effect’. Their antibacterial effect consists of the inhibition of bacterial protein synthesis, impaired bacterial biofilm synthesis, and the attenuation of other bacterial virulence factors. Apart from these direct antimicrobial effects, macrolides are known for their modulating effect on many components of the human immune system. By influencing the production of cytokines, they have a dampening effect on the proinflammatory response. Furthermore, the majority of cells involved in the immune response are, in one way or another, influenced when macrolide antibiotics are administered. Having such an obvious effect on the various aspects of the immune system, macrolides seem to be exceptionally suited for the treatment of chronic inflammatory diseases.

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Influence of Macrolide Susceptibility on Efficacies of Clarithromycin and Azithromycin against Streptococcus pneumoniae in a Murine Lung Infection Model

Cited by 32 publications

References 19 publications

Effects of macrolides on pneumolysin of macrolide-resistantStreptococcus pneumoniae

Effects of macrolides on pneumolysin of macrolide-resistantStreptococcus pneumoniae

Roxithromycin Favorably Modifies the Initial Phase of Resistance against Infection with Macrolide-Resistant Streptococcus pneumoniae in a Murine Pneumonia Model

Immunomodulatory Effects of Macrolide Antibiotics – Part 1: Biological Mechanisms

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