macrolide effects on

download macrolide effects on

of 26

  • date post

    22-Dec-2015
  • Category

    Documents

  • view

    231
  • download

    4

Embed Size (px)

Transcript of macrolide effects on

  • CLINICAL MICROBIOLOGY REVIEWS, July 2010, p. 590615 Vol. 23, No. 30893-8512/10/$12.00 doi:10.1128/CMR.00078-09Copyright 2010, American Society for Microbiology. All Rights Reserved.

    Mechanisms of Action and Clinical Application of Macrolidesas Immunomodulatory Medications

    Soichiro Kanoh and Bruce K. Rubin*Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Virginia

    INTRODUCTION .......................................................................................................................................................591NONANTIMICROBIAL EFFECTS..........................................................................................................................591Effects on Airway Secretion ...................................................................................................................................591Ion transport .......................................................................................................................................................591Mucus secretion ..................................................................................................................................................591

    Effects on Inflammation.........................................................................................................................................592Cytokine production ...........................................................................................................................................592Adhesion molecule expression...........................................................................................................................593Inflammatory cells ..............................................................................................................................................593(i) Chemotaxis .................................................................................................................................................593(ii) Chemical mediators .................................................................................................................................593(iii) ROS...........................................................................................................................................................594(iv) Apoptosis ..................................................................................................................................................594(v) Cell differentiation....................................................................................................................................594

    Airway epithelial cells ........................................................................................................................................594(i) Epithelial barrier.......................................................................................................................................594(ii) CFTR expression......................................................................................................................................594(iii) TLRs .........................................................................................................................................................595

    Other cells............................................................................................................................................................595(i) Fibroblasts..................................................................................................................................................595(ii) Vascular endothelial cells .......................................................................................................................595

    Effects on Cell Signaling........................................................................................................................................595Intracellular calcium..........................................................................................................................................595MAPKs .................................................................................................................................................................596Transcription factors .......................................................................................................................................................597

    EFFECTS ON BACTERIA ........................................................................................................................................597Inhibition of Adherence .........................................................................................................................................597Inhibition of Virulence Factors.............................................................................................................................598Inhibition of Biofilms .............................................................................................................................................598Inhibition of Quorum Sensing ..............................................................................................................................599

    SUMMARY OF MECHANISMS OF IMMUNOMODULATION........................................................................600CLINICAL EFFECTS.................................................................................................................................................600Asthma......................................................................................................................................................................600Non-CF Bronchiectasis ..........................................................................................................................................601COPD .......................................................................................................................................................................602Chronic Rhinosinusitis ..........................................................................................................................................602CF..............................................................................................................................................................................603DPB...........................................................................................................................................................................603Influenza and Sepsis ..............................................................................................................................................604Posttransplantation BOS.......................................................................................................................................605

    SAFETY OF LONG-TERM MACROLIDE THERAPY.........................................................................................605Macrolide Resistance .............................................................................................................................................605Long-Term Macrolide Safety.................................................................................................................................605

    OTHER RELATED DRUGS .....................................................................................................................................606Ketolides...................................................................................................................................................................606Quinolones ...............................................................................................................................................................606EM703 ......................................................................................................................................................................607

    CONCLUSIONS .........................................................................................................................................................607REFERENCES ............................................................................................................................................................607

    * Corresponding author. Mailing address: Department of Pediatrics,Virginia Commonwealth University School of Medicine, 1001 E. Mar-shall St., Richmond, VA 23298. Phone: (804) 828-9604. Fax: (804)828-2062. E-mail: brubin@vcu.edu.

    590

    on M

    arch 31, 2015 by guesthttp://cm

    r.asm.org/

    Dow

    nloaded from

  • INTRODUCTION

    The term macrolide is used to describe drugs with a mac-rocyclic lactone ring of 12 or more elements (183). This class ofcompounds includes a variety of bioactive agents, includingantibiotics, antifungal drugs, prokinetics, and immunosuppres-sants. The 14-, 15-, and 16-membered macrolides are a widelyused family of antibiotics. They have excellent tissue penetra-tion and antimicrobial activity, mainly against Gram-positivecocci and atypical pathogens (27). Macrolide concentrationsare at least 10-fold higher in the epithelial lung fluid than inserum. Erythromycin A, a 14-membered macrolide, was isolatedmore than 50 years ago from cultures of Streptomyces and was thefirst macrolide introduced into clinical practice (183, 325). In thisreview, macrolide antibiotics are called macrolides.

    The nonantimicrobial properties of macrolides were sus-pected as far back as the 1960s (110), but their dramatic clin-ical effectiveness in treating diffuse panbronchiolitis (DPB) hasserved to extend their use to a number of chronic inflammatorydiseases (71, 157, 202). DPB is a chronic debilitating disorderof unknown etiology primarily