Clinical Infectious Diseases Advance Access published May 21, 2015
EDITORIAL COMMENTARY
Vaginal Biofilm: Much Ado About Nothing, or a New Therapeutic Challenge? Jack D. Sobel Wayne State University School of Medicine, Detroit, Michigan
Keywords.
biofilm; bacterial vaginosis; vulvovaginal candidiasis; vaginitis
Received 23 April 2015; accepted 24 April 2015. Correspondence: Jack D. Sobel, MD, Wayne State University School of Medicine, 1241 Scott Hall, 540 E Canfield St, Detroit, MI 48201 ( [email protected]). Clinical Infectious Diseases® © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/civ358
the epithelial surface–associated biofilm. Thus, in contrast to related planktonic microorganisms, bacterial communities within the biofilm persist long after the antimicrobial threat is removed and often with an altered phenotype, growth rate, and gene transcription. As such, persistent colonization of the vagina follows and provides a reservoir for even sensitive pathogens to remain in situ. As a consequence of impaired suboptimal penetration of antibiotics, biofilm-embedded bacteria are exposed to lower-than-desired concentrations of antibiotic, allowing for the development of antibiotic resistance. A further consequence of the biofilm is potential interference with bacterial–epithelial cell receptor interaction, thus influencing the generation of intracellular signaling in creating the desirable innate immune inflammatory response. In the final analysis, biofilm-contained microorganisms are permitted to evade not only the curative therapeutic effect of antibiotics but also host defense mechanisms. This sets the stage for incomplete response to antibiotics and repeated relapses as opposed to frequent reinfection. As such, biofilms provide a sanctuary for difficult-to-eradicate pathogens. The adherent polymicrobial biofilm present in virtually all women with bacterial vaginosis (BV) has been observed and confirmed by multiple researchers [3]. The evidence is considerable and is well described by Muzny and Schwebke [1].
Following the demonstration of polymicrobial, but predominantly Gardnerella vaginalis biofilm in vivo, in vitro models followed and convincingly demonstrated that biofilm containing G. vaginalis is more resistant not only to antibiotics but also to the protective mechanisms of the normal vaginal microbiome—namely, pH, lactic acid, and hydrogen peroxide—once more creating an environment conducive to chronicity and frequent relapse of symptomatic BV. The demonstration of a similar polymicrobial biofilm in the urethra of male partners of women with BV energized current hypotheses regarding the role of sexual transmission in causation of BV [4]. As such, the never-ending argument regarding treating male partners of women with recurrent BV was reignited. Although considerable progress has been made in the treatment of BV, no satisfactory treatment solution for the frequent recurrences of BV has been forthcoming. Several antibiotic regimens are now recommended as long-term-maintenance suppressive therapy that reasonably control and prevent symptomatic recurrence, but remain far from providing rapid and high cure rates [5]. The first clue that treatment of recurrent BV with an agent that removed biofilm might enhance cure rates was suggested by Reichman et al in 2009 using topical boric acid [6]. Currently based on growing evidence of the critical role of biofilm, numerous and diverse
EDITORIAL COMMENTARY
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CID
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1
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on May 25, 2015
Every few years, a new clinical pathologic entity emerges that serves as a popular bandwagon attracting a wave of enthusiastic research and reporting. Is biofilm the latest bandwagon? We are reminded in the text of the article by Muzny and Schwebke, in this issue of Clinical Infectious Diseases, that biofilms are microbial communities embedded in a self-produced extracellular matrix attached to an inert or superficial cellular surface [1]. Although first described as forming on abiotic nonsterile surfaces (eg, pipes) and subsequently on catheters or foreign bodies in clinical use (eg, Foley or intravascular catheters, articular prostheses), biofilms were more recently reported in vivo on active epithelial or mucosal surfaces, such as the oral mucosa and the vagina [2]. Muzny and Schwebke should be congratulated for providing a superb review of the biofilm and its role in vaginal infection. The importance of biofilm relates to several pathologic characteristics. First, microorganisms embedded in the extracellular matrix are protected from some antimicrobials that may fail to penetrate
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CID
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EDITORIAL COMMENTARY
RVVC. Multiple human vaginal biopsy studies performed by Swidsinski have never shown any evidence of biofilm in VVC (A. Swidsinski, oral communication). Virtually all the in vivo support for a Candida biofilm originates from the oral cavity with clinical oral candidiasis dissimilar from VVC. A biofilm containing Candida covering enamel or dental surface is indisputable. However, the vast majority of published studies dealing with Candida biofilm are based on in vitro studies conducted in multiwell chambers. A physical biofilm visible to the naked eye is so created. Limited data derived from the murine model of VVC suggest the existence of an in vivo Candida biofilm containing a mesh of adherent hyphae with a superimposed polysaccharide matrix; however, the physical conditions of the experimental model differ considerably from that of women [12]. Also quoted in the argument for biofilm in VVC is the therapeutic effect of boric acid. Boric acid is infrequently used to treat VVC and is almost never useful in RVVC, being indicated only for fluconazole-resistant yeast (eg, C. glabrata). Boric acid actually has direct antimycotic activity measureable in vitro in the absence of a pathogenic biofilm and has never been shown to facilitate treatment of RVVC caused by azole-sensitive species of Candida. Therefore, the evidence supporting a role for biofilm in RVVC remains speculative at best. Biofilm is not a transient “bandwagon”; its role in the pathogenesis of chronic refractory prosthesis, catheter, and valve infections is undeniable, and likely has an important role in BV. This conclusion is emphasized by the current standstill in therapeutic progress in the treatment of recurrent BV. The results of new innovative clinical techniques targeting biofilm in BV are eagerly awaited.
Note Potential conflict of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. Muzny CA, Schwebke JR. Biofilms: an underappreciated mechanism of treatment failure and recurrence in vaginal infections. Clin Infect Dis 2015; doi:10.1093/cid/civ353. 2. Costerton W, Veeh R, Shirthff M, Pasmore M, Post C, Ehrlich G. The application of biofilm science to the study and control of chronic bacterial infections. J Clin Invest 2003; 112:1466–77. 3. Swidsinski A, Mendling W, Loening-Baucke V, et al. Adherent biofilms in bacterial vaginosis. Obstet Gynecol 2005 106:1013–23. 4. Swidsinski A, Doerffel Y, Loening-Baucke V, et al. Gardnerella biofilm involves females and males and is transmitted sexually. Gynecol Obstet Invest 2010; 70:256–63. 5. Sobel JD, Ferris D, Schwebke J, et al. Suppressive antibacterial therapy with 0.75% metronidazole vaginal gel to prevent recurrent bacterial vaginosis. Am J Obstet Gynecol 2006; 194:1283–9. 6. Reichman O, Akins R, Sobel JD. Boric acid addition to suppressive antimicrobial therapy for recurrent bacterial vaginosis. Sex Transm Dis 2009; 36:732–4. 7. Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Candida vaginitis: self-reported incidence and associated costs. Sex Transm Dis 2000; 27:230–5. 8. Foxman B, Muraglia R, Dietz JP, Sobel JD, Wagner J. Prevalence of recurrent vulvovaginal candidiasis in 5 European countries and the United States: results from an internet panel survey. J Low Genit Tract Dis 2013; 17:340–5. 9. Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med 2004; 351:876–83. 10. Donders G, Bellen G, Byttebier G, et al. Individualized decreasing-dose maintenance fluconazole regimen for recurrent vulvovaginal candidiasis (ReCiDiF trial). Am J Obstet Gynecol 2008; 199:613.e1-9. 11. Rosentul DC, Delsing CE, Jaeger M, et al. Gene polymorphisms in pattern recognition receptors and susceptibility to idiopathic recurrent vulvovaginal candidiasis. Front Microbiol 2014; 5:483. 12. Harriott MM, Lilly EA, Rodriguez TE, et al. Candida albicans forms biofilms on the vaginal mucosa. Microbiology 2010; 156:3635–44.
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on May 25, 2015
agents, often in combination, are being studied in clinical trials. Frustrated clinicians and patients alike eagerly await the outcome of these studies. Epidemiologic studies to quantify the burden of recurrent vulvovaginal candidiasis (RVVC) have been few in number and are profoundly flawed by the availability of over-the-counter topical antimycotics and the prevailing “presumptive-style” diagnostic methodology on the part of practitioners. Nevertheless, 2 large studies performed 2 decades apart and using entirely different methodologies came to an identical conclusion—namely, that approximately 6%–9% of women of reproductive age report suffering from RVVC, with ≥3 attacks of vulvovaginal candidiasis (VVC) annually [7, 8]. Currently, RVVC in these women is well controlled by the long-term administration of weekly prophylactic oral fluconazole; however, cure is elusive [9, 10]. No definitive curative method is available; moreover, no clear understanding of the pathogenesis of RVVC exists. The yeast involved, usually Candida albicans, remains sensitive, and women are otherwise healthy and do not suffer from candidiasis at other sites; although triggers for acute recurrent bouts of VVC differ, there is growing evidence of a polygenetic underlying basis for RVVC [11]. Regardless of the genetic mechanism involved in causation of RVVC, there is also some suggestion of vaginal persistence of yeast pathogens. Following antifungal treatment, women with RVVC are more likely to remain colonized with fluconazole-susceptible organisms. This fact alone has generated belief in the possible existence of a yeast-containing vaginal biofilm enabling yeast persistence. Unfortunately, the considerable data available on the in vivo biofilm in BV simply have never been duplicated or seen in the vagina of women with VVC or
EDITORIAL COMMENTARY
Vaginal Biofilm: Much Ado About Nothing, or a New Therapeutic Challenge? Jack D. Sobel Wayne State University School of Medicine, Detroit, Michigan
Keywords.
biofilm; bacterial vaginosis; vulvovaginal candidiasis; vaginitis
Received 23 April 2015; accepted 24 April 2015. Correspondence: Jack D. Sobel, MD, Wayne State University School of Medicine, 1241 Scott Hall, 540 E Canfield St, Detroit, MI 48201 ( [email protected]). Clinical Infectious Diseases® © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/civ358
the epithelial surface–associated biofilm. Thus, in contrast to related planktonic microorganisms, bacterial communities within the biofilm persist long after the antimicrobial threat is removed and often with an altered phenotype, growth rate, and gene transcription. As such, persistent colonization of the vagina follows and provides a reservoir for even sensitive pathogens to remain in situ. As a consequence of impaired suboptimal penetration of antibiotics, biofilm-embedded bacteria are exposed to lower-than-desired concentrations of antibiotic, allowing for the development of antibiotic resistance. A further consequence of the biofilm is potential interference with bacterial–epithelial cell receptor interaction, thus influencing the generation of intracellular signaling in creating the desirable innate immune inflammatory response. In the final analysis, biofilm-contained microorganisms are permitted to evade not only the curative therapeutic effect of antibiotics but also host defense mechanisms. This sets the stage for incomplete response to antibiotics and repeated relapses as opposed to frequent reinfection. As such, biofilms provide a sanctuary for difficult-to-eradicate pathogens. The adherent polymicrobial biofilm present in virtually all women with bacterial vaginosis (BV) has been observed and confirmed by multiple researchers [3]. The evidence is considerable and is well described by Muzny and Schwebke [1].
Following the demonstration of polymicrobial, but predominantly Gardnerella vaginalis biofilm in vivo, in vitro models followed and convincingly demonstrated that biofilm containing G. vaginalis is more resistant not only to antibiotics but also to the protective mechanisms of the normal vaginal microbiome—namely, pH, lactic acid, and hydrogen peroxide—once more creating an environment conducive to chronicity and frequent relapse of symptomatic BV. The demonstration of a similar polymicrobial biofilm in the urethra of male partners of women with BV energized current hypotheses regarding the role of sexual transmission in causation of BV [4]. As such, the never-ending argument regarding treating male partners of women with recurrent BV was reignited. Although considerable progress has been made in the treatment of BV, no satisfactory treatment solution for the frequent recurrences of BV has been forthcoming. Several antibiotic regimens are now recommended as long-term-maintenance suppressive therapy that reasonably control and prevent symptomatic recurrence, but remain far from providing rapid and high cure rates [5]. The first clue that treatment of recurrent BV with an agent that removed biofilm might enhance cure rates was suggested by Reichman et al in 2009 using topical boric acid [6]. Currently based on growing evidence of the critical role of biofilm, numerous and diverse
EDITORIAL COMMENTARY
•
CID
•
1
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on May 25, 2015
Every few years, a new clinical pathologic entity emerges that serves as a popular bandwagon attracting a wave of enthusiastic research and reporting. Is biofilm the latest bandwagon? We are reminded in the text of the article by Muzny and Schwebke, in this issue of Clinical Infectious Diseases, that biofilms are microbial communities embedded in a self-produced extracellular matrix attached to an inert or superficial cellular surface [1]. Although first described as forming on abiotic nonsterile surfaces (eg, pipes) and subsequently on catheters or foreign bodies in clinical use (eg, Foley or intravascular catheters, articular prostheses), biofilms were more recently reported in vivo on active epithelial or mucosal surfaces, such as the oral mucosa and the vagina [2]. Muzny and Schwebke should be congratulated for providing a superb review of the biofilm and its role in vaginal infection. The importance of biofilm relates to several pathologic characteristics. First, microorganisms embedded in the extracellular matrix are protected from some antimicrobials that may fail to penetrate
2
•
CID
•
EDITORIAL COMMENTARY
RVVC. Multiple human vaginal biopsy studies performed by Swidsinski have never shown any evidence of biofilm in VVC (A. Swidsinski, oral communication). Virtually all the in vivo support for a Candida biofilm originates from the oral cavity with clinical oral candidiasis dissimilar from VVC. A biofilm containing Candida covering enamel or dental surface is indisputable. However, the vast majority of published studies dealing with Candida biofilm are based on in vitro studies conducted in multiwell chambers. A physical biofilm visible to the naked eye is so created. Limited data derived from the murine model of VVC suggest the existence of an in vivo Candida biofilm containing a mesh of adherent hyphae with a superimposed polysaccharide matrix; however, the physical conditions of the experimental model differ considerably from that of women [12]. Also quoted in the argument for biofilm in VVC is the therapeutic effect of boric acid. Boric acid is infrequently used to treat VVC and is almost never useful in RVVC, being indicated only for fluconazole-resistant yeast (eg, C. glabrata). Boric acid actually has direct antimycotic activity measureable in vitro in the absence of a pathogenic biofilm and has never been shown to facilitate treatment of RVVC caused by azole-sensitive species of Candida. Therefore, the evidence supporting a role for biofilm in RVVC remains speculative at best. Biofilm is not a transient “bandwagon”; its role in the pathogenesis of chronic refractory prosthesis, catheter, and valve infections is undeniable, and likely has an important role in BV. This conclusion is emphasized by the current standstill in therapeutic progress in the treatment of recurrent BV. The results of new innovative clinical techniques targeting biofilm in BV are eagerly awaited.
Note Potential conflict of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. Muzny CA, Schwebke JR. Biofilms: an underappreciated mechanism of treatment failure and recurrence in vaginal infections. Clin Infect Dis 2015; doi:10.1093/cid/civ353. 2. Costerton W, Veeh R, Shirthff M, Pasmore M, Post C, Ehrlich G. The application of biofilm science to the study and control of chronic bacterial infections. J Clin Invest 2003; 112:1466–77. 3. Swidsinski A, Mendling W, Loening-Baucke V, et al. Adherent biofilms in bacterial vaginosis. Obstet Gynecol 2005 106:1013–23. 4. Swidsinski A, Doerffel Y, Loening-Baucke V, et al. Gardnerella biofilm involves females and males and is transmitted sexually. Gynecol Obstet Invest 2010; 70:256–63. 5. Sobel JD, Ferris D, Schwebke J, et al. Suppressive antibacterial therapy with 0.75% metronidazole vaginal gel to prevent recurrent bacterial vaginosis. Am J Obstet Gynecol 2006; 194:1283–9. 6. Reichman O, Akins R, Sobel JD. Boric acid addition to suppressive antimicrobial therapy for recurrent bacterial vaginosis. Sex Transm Dis 2009; 36:732–4. 7. Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Candida vaginitis: self-reported incidence and associated costs. Sex Transm Dis 2000; 27:230–5. 8. Foxman B, Muraglia R, Dietz JP, Sobel JD, Wagner J. Prevalence of recurrent vulvovaginal candidiasis in 5 European countries and the United States: results from an internet panel survey. J Low Genit Tract Dis 2013; 17:340–5. 9. Sobel JD, Wiesenfeld HC, Martens M, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med 2004; 351:876–83. 10. Donders G, Bellen G, Byttebier G, et al. Individualized decreasing-dose maintenance fluconazole regimen for recurrent vulvovaginal candidiasis (ReCiDiF trial). Am J Obstet Gynecol 2008; 199:613.e1-9. 11. Rosentul DC, Delsing CE, Jaeger M, et al. Gene polymorphisms in pattern recognition receptors and susceptibility to idiopathic recurrent vulvovaginal candidiasis. Front Microbiol 2014; 5:483. 12. Harriott MM, Lilly EA, Rodriguez TE, et al. Candida albicans forms biofilms on the vaginal mucosa. Microbiology 2010; 156:3635–44.
Downloaded from http://cid.oxfordjournals.org/ at Florida Atlantic University on May 25, 2015
agents, often in combination, are being studied in clinical trials. Frustrated clinicians and patients alike eagerly await the outcome of these studies. Epidemiologic studies to quantify the burden of recurrent vulvovaginal candidiasis (RVVC) have been few in number and are profoundly flawed by the availability of over-the-counter topical antimycotics and the prevailing “presumptive-style” diagnostic methodology on the part of practitioners. Nevertheless, 2 large studies performed 2 decades apart and using entirely different methodologies came to an identical conclusion—namely, that approximately 6%–9% of women of reproductive age report suffering from RVVC, with ≥3 attacks of vulvovaginal candidiasis (VVC) annually [7, 8]. Currently, RVVC in these women is well controlled by the long-term administration of weekly prophylactic oral fluconazole; however, cure is elusive [9, 10]. No definitive curative method is available; moreover, no clear understanding of the pathogenesis of RVVC exists. The yeast involved, usually Candida albicans, remains sensitive, and women are otherwise healthy and do not suffer from candidiasis at other sites; although triggers for acute recurrent bouts of VVC differ, there is growing evidence of a polygenetic underlying basis for RVVC [11]. Regardless of the genetic mechanism involved in causation of RVVC, there is also some suggestion of vaginal persistence of yeast pathogens. Following antifungal treatment, women with RVVC are more likely to remain colonized with fluconazole-susceptible organisms. This fact alone has generated belief in the possible existence of a yeast-containing vaginal biofilm enabling yeast persistence. Unfortunately, the considerable data available on the in vivo biofilm in BV simply have never been duplicated or seen in the vagina of women with VVC or
