|Bacterial vaginosis, Atopobium vaginae and nifuratel.|
|Jump to Full Text|
|PMID: 22082330 Owner: NLM Status: MEDLINE|
|As bacterial vaginosis (BV) is a potential cause of obstetric complications and gynecological disorders, there is substantial interest in establishing the most effective treatment. Standard treatment - metronidazole or clindamycin, by either vaginal or oral route � is followed by relapses in about 30% of cases, within a month from treatment completion. This inability to prevent recurrences reflects our lack of knowledge on the origins of BV. Atopobium vaginae has been recently reported to be associated with BV in around 80% of the cases and might be involved in the therapeutic failures. This review looks at the potential benefits of nifuratel against A. vaginae compared to the standard treatments with metronidazole and clindamycin. In vitro, nifuratel is able to inhibit the growth of A. vaginae, with a MIC range of 0.125-1 μg/mL; it is active against G. vaginalis and does not affect lactobacilli. Metronidazole is active against A. vaginae only at very high concentrations (8-256 μg/mL); it is partially active against G. vaginalis and also has no effect on lactobacilli. Clindamycin acts against A. vaginae with an MIC lower than 0.125 μg/mL and is active on G. vaginalis but it also affects lactobacilli, altering the vaginal environment. These observations suggest that nifuratel is probably the most valid therapeutic agent for BV treatment.|
|Type: Comparative Study; Journal Article; Review|
|Title: Current clinical pharmacology Volume: 7 ISSN: 2212-3938 ISO Abbreviation: Curr Clin Pharmacol Publication Date: 2012 Feb|
|Created Date: 2012-02-03 Completed Date: 2012-05-25 Revised Date: 2013-03-01|
Medline Journal Info:
|Nlm Unique ID: 101273158 Medline TA: Curr Clin Pharmacol Country: United Arab Emirates|
|Languages: eng Pagination: 36-40 Citation Subset: IM|
|Department of Obstetrics and Gynecology, Policlinico San Matteo, University of Pavia, Pavia, Italy. firstname.lastname@example.org|
|APA/MLA Format Download EndNote Download BibTex|
isolation & purification
Anti-Bacterial Agents / administration & dosage, pharmacology, therapeutic use
Clindamycin / administration & dosage, pharmacology, therapeutic use
Dose-Response Relationship, Drug
Gardnerella vaginalis / drug effects, isolation & purification
Metronidazole / administration & dosage, pharmacology, therapeutic use
Microbial Sensitivity Tests
Nifuratel / administration & dosage, pharmacology, therapeutic use*
Recurrence / prevention & control
Vaginosis, Bacterial / drug therapy*, microbiology
|0/Anti-Bacterial Agents; 18323-44-9/Clindamycin; 443-48-1/Metronidazole; 4936-47-4/Nifuratel|
Journal ID (nlm-ta): Curr Clin Pharmacol
Journal ID (iso-abbrev): Curr Clin Pharmacol
Journal ID (publisher-id): CCP
Publisher: Bentham Science Publishers
© 2012 Bentham Science Publishers
Received Day: 5 Month: 6 Year: 2011
Revision Received Day: 5 Month: 10 Year: 2011
Accepted Day: 20 Month: 10 Year: 2011
Print publication date: Month: 2 Year: 2012
Electronic publication date: Month: 2 Year: 2012
Volume: 7 Issue: 1
First Page: 36 Last Page: 40
PubMed Id: 22082330
Publisher Id: CCP-7-36
|Bacterial Vaginosis, Atopobium vaginae and Nifuratel|
|Department of Obstetrics and Gynecology, Policlinico San Matteo, University of Pavia, Pavia, Italy
|*Address correspondence to this author at the Department of Obstetrics and
Gynecology, Policlinico San Matteo, University of Pavia, Piazzale Golgi 2,
27100 Pavia, Pavia, Italy; Tel: +39 524309; Fax: +39 524309;
Bacterial vaginosis (BV) is one of the most frequent female lower genital tract infections, not only in pregnancy but throughout the reproductive life. Studies from Europe and the USA have found prevalence between 4.9% and 36.0% . The first signs of BV are radical changes in the vaginal ecosystem. H202-producing lactobacilli, which are present in 96% of women with normal vaginal bacterial flora, are markedly reduced or lost, while microorganisms like Gardnerella vaginalis and obligate anaerobes prevail . The cause of this change is not clear  and the microorganisms responsible for the shift in the flora have still to be identified . BV may be due not only to the excessive bacterial growth, but also to the formation of a dense bacterial biofilm adherent to the vaginal mucosa.
The biofilm formed by Gardnerellavaginalis in BV was first identified by electron microscopy as a dense tissue strongly adherent to the vaginal epithelium, and made up of bacterial cells packed inside a network of polysaccharide fibrils [5, 6]. Later, Swidsinki et al., investigating vaginal biopsies by bacterial rDNA fluorescent in situ hybridization, suggested that the bacterial biofilm played a primary role in the development of BV .
Costerton et al. and Swidsinki et al. found a dense bacterial biofilm, coating at least half the epithelial surface, in 90% of biopsies from women with BV, and in only 10% of healthy women [7, 8]. The presence of the biofilm enables the bacterial cells to reach higher concentrations (up to 1011 bacteria/mL) than in vaginal fluid and boosts their resistance to both the host immune system and the antimicrobials [9, 10]. In fact, the drugs hardly reach the bacteria, residing inside the film in a quiescent state, leading to an up to 1000-fold antimicrobial decreased activity [9, 11]. This observation might provide an explanation of the high rates of BV relapses [10, 12].
BV has aroused interest in the last few years being considered as a predisposing factor for HIV, Type II Herpes symplex virus, Chlamydia trachomatis infections, as well as for trichomoniasis and gonorrhea [13, 14]; BV can be also a cause for complications like late abortion , premature rupture of the amniotic membrane , chorio-amnionitis , post-partum endometritis [18, 19, 20], and failure of in vitro fertilization and embryo transfer [13, 14]. Particular attention has been recently paid to Atopobium vaginae, a newly identified bacterium, belonging to the Coriobacteriaceae family, which is believed to be at least a partial cause of the above mentioned complications . The genus Atopobium, described for the first time in 1992, includes bacteria previously classified as lactobacilli. Rodriguez first identified A. vaginae in a study on vaginal lactobacilli . A. vaginae 16s rRNA gene differs from the other species belonging to Atopobium genus by approximately 3-8% [22, 23]; this enabled Rodriguez to identify it as a new species. The isolate can be distinguished from A. minutum, A. parvulum, and A. rimae by biochemical tests and protein electrophoresis of the whole cell (Table 1). Gram stain shows A. vaginae as a small coccus, rounded or oval, or rods, visible as single cells, in pairs or in short chains (Fig. 1).
This aerobic facultative, gram-positive bacterium cannot be easily isolated by classical microbiological methods [14, 24]. It is hardly detected in healthy women vaginal fluid but is commonly found in the vagina of patients with BV: 50% according to Burton [25, 26], 70% according to Ferris , and more than 95% according to Verhelst et al.  and Verstraelen et al. . In symptomatic BV it has been detected together with Gardnerella vaginalis in the biofilm adherent to the vaginal mucosa . This was confirmed by Swidsinski et al.  who, by examining the composition and structural organization of the biofilm, found that Gardnerella vaginalis accounted for 60-95% of the film mass. In addition, in 70% of bioptic samples, Atopobium vaginae accounted for the 1-40% of the film mass. Lactobacillus concentrations were lower than 106 CFU/mL, making up only 5% of the biofilm (Fig. 2).
Concerning the pharmacological therapy, CDC recommends either oral or topical (vaginal gel) metronidazole once a day for 5 days as first choice for BV. Efficacy is comparable to topical clindamycin . Cure rates, following intravaginal treatment with metronidazole or clindamycin, account for 80-90% at the end of treatment and one month after the end of therapy [13, 14, 30]. However, three months after the end of therapy the rate of relapses can overcome 30%. Persistence of an adherent bacterial biofilm, containing mostly G. vaginalis and A. vaginae, seems to be the main reason for failure of BV treatment . Suppressive treatment with metronidazole gel and physiological approaches (use of probiotics or acidifying) have been investigated with variable results . Moreover, long-term treatment with metronidazole is not recommended because of the high incidence of gastrointestinal adverse reactions, the risk of peripheral neuropathy, and Candida super infection .
Failures with metronidazole in patients with recurrent or persistent BV [33, 34] might conceivably reflect the newly found mechanism of formation of a biofilm containing G. vaginalis together with A. vaginae [7, 9, 13, 28] (Fig. 3). The fact that A. vaginae is resistant to metronidazole, and that the bacterium creates a biofilm in which it is associated with G. vaginalis, complicates the response to the antibiotic [9, 13, 28]. Though clindamycin is more active than metronidazole against both G. vaginalis and A. vaginae, its negative effects on lactobacilli leave the way open to microbial disorders that can cause frequent super infections and recurrences. Moreover, an increasing resistance to antibiotics that act like clindamycin, by blocking protein synthesis has been reported. A randomized prospective trial compared 119 women assigned to two therapeutic regimens for BV: either metronidazole vaginal gel for five days, or clindamycin vaginal tablets for three days. The clinical efficacy was comparable in the two arms: after 7-12 days about 80% of the patients were cured, but this percentage fell down to about 50% after 35-45 days. Following clindamycin treatment – but not metronidazole - there was a steep rise in the percentage of women with at least one clindamycin resistant strain isolated. Moreover, 70-90 days after the end of treatment, about 80% of the women who received clindamycin presented in their vaginal swabs anaerobic bacteria resistant to that drug .
Togni et al.  compared the in vitro susceptibility of A. vaginae to nifuratel, metronidazole and clindamycin. Susceptibility to metronidazole was variable, with MIC ranging from 8 to 256 µg/mL. Nifuratel and clindamycin inhibited the growth of all the tested strains, with MIC from 0.125 to 1 µg/mL and below 0.125 µg/mL, respectively (Table 2). The findings related to metronidazole and clindamycin are in line with previously published studies .
In the same study, the activity of these antibiotics was assayed on lactobacilli and G. vaginalis. Either nifuratel and metronidazole did not affect the normal lactobacterial flora, while clindamycin inhibited all tested strains of lactobacilli. Nifuratel and metronidazole were both highly active against G. vaginalis (Fig. 4). The susceptibility of Atopobium vaginae to metronidazole and clindamycin, and the action on lactobacilli and G. vaginalis were in line with previous reports [37-39]. To summarise, nifuratel was active against A. vaginae and G. vaginalis strains without affecting lactobacilli; metronidazole was active against A. vaginae, but only at very high concentrations, partially active against G. vaginalis, and did not affect lactobacilli; clindamycin was extremely effective against A. vaginae and G. vaginalis, but it also affected the lactobacilli, altering the vaginal ecosystem.
The discovery of the presence of Atopobium vaginae in the vaginal ecosystem improves the basic understanding of the pathogenesis of BV . This bacterium is presumably the main reason for failures or recurrences after BV treatment with metronidazole, since it is found in 80-90% of cases of relapse . Prospective studies are now needed to show whether metronidazole–resistant microorganisms, such as Atopobium vaginae, are involved in recurrences. Information to date suggests that nifuratel is probably the most valid therapeutic agent for BV, as it is highly active against Gardnerella vaginalis and Atopobium vaginae, without affecting lactobacilli which are fundamental for the system health and balance .
|1.||Morris M,Nicoll A,Simms I,Wilson J,Catchpole M. Bacterial vaginosis: a public health reviewBJOGYear: 20011084395011368127|
|2.||Nam H,Whang K,Lee Y. Analysis of vaginal lactic acid producing bacteria in healthy womenJ MicrobiolYear: 2007455152018176534|
|3.||Cauci S,Monte R,Driussi S,Lanzafame P,Quadrifoglio F. Impairment of the mucosal immune system: IgA and IgM cleavage detected in vaginal washing of a subgroup of patients with bacterial vaginosisJ Infect DisYear: 1998178169817069815222|
|4.||Sobel JD. Bacterial vaginosisAnnu Rev MedYear: 2000513495610774469|
|5.||van der Meijden WI,Koerten H,van Mourik W,de Bruijn WC. Descriptive light and electron microscopy of normal and clue-cell-positive dischargeGynecol Obstet InvestYear: 19882547573257743|
|6.||Scott TG,Curran B,Smyth CJ. Electron microscopy of adhesive interactions between Gardnerella vaginalis and vaginal epithelial cells, McCoy cells and human red blood cellsJ Gen Microbiol Year: 1989135475802576032|
|7.||Swidsinki A,Mendling W,Loening-Baucke V,Ladhoff A,Swidsinki S,Hale LP,Lochs H. Adherent biofilms in bacterial vaginosisObstet GynecolYear: 200510610132316260520|
|8.||Costerton W,Veeh R,Shirtliff M,Pasmore M,Post C,Ehrlich G. The application of biofilm science to the study and control of chronic bacterial infectionsJ Clin InvestYear: 200311214667714617746|
|9.||Swidsinki A,Mendling W,Loening-Baucke V,Swidsinski S,Dörffel Y,Scholze J,Lochs H,Verstraelen H. An adherent Gardnerella vaginalis biofilm persists on the vaginal epithelium after standard therapy with metronidazoleAm J Obstet Gynecol Year: 200819897.e1-618005928|
|10.||Hay P. Recurrent bacterial vaginosisCurr Infect Dis RepYear: 200025061211095900|
|11.||Hoiby N,Bjarnsholt T,Givskov M,Molin S,Ciofu O. Antibiotic resistance of bacterial biofilmsInt J Antimicrob AgentsYear: 2010353223220149602|
|12.||Pirotta M,Fethers KA,Bradshaw CS. Bacterial vaginosis - More questions than answersAust Fam PhysicianYear: 200938394719521581|
|13.||Fredricks DN,Fiedler TL,Marrazzo JM. Molecular identification of bacteria associated with bacterial vaginosisN Engl J MedYear: 2005353189991116267321|
|14.||Livengood CH. Bacterial vaginosis: an overview for 2009Rev Obstet GynecolYear: 20092283719399292|
|15.||Donati L,Di Vico A,Nucci M,Quagliozzi L,Spagnuolo T,Labianca A,Bracaglia M,Ianniello F,Caruso A,Paradisi G. Vaginal microbial flora and outcome of pregnancyArch Gynecol ObstetYear: 201028158960019967381|
|16.||McDonald HM,Brocklehurst P,Gordon A. Antibiotics for treating bacterial vaginosis in pregnancyCochrane Database Syst Rev Year: 2007241 (CD000262).|
|17.||Fahey JO. Clinical management of intra-amniotic infection and chorioamnionitis: a review of the literatureJ Midwifery Women’s HealthYear: 20085322735|
|18.||Hillier SL,Kiviat NB,Hawes SE,Hasselquist MB,Hanssen PW,Eschenbach DA,Holmes KK. Role of bacterial vaginosis-associated microorganisms in endometritisAm J Obstet Gynecol Year: 1996175435418765265|
|19.||Sweet RL. Role of bacterial vaginosis in pelvic inflammatory diseaseClin Infect DisYear: 199520S27157548573|
|20.||Pellati D,Mylonakis I,Bertoloni G,Fiore C,Andrisani A,Ambrosini G,Armanini D. Genital tract infections and infertilityEur J Obstet Gynecol Reprod BiolYear: 200814031118456385|
|21.||Rodriguez Jovita M,Collins MD,Sjoden B,Falsen E. Characterization of a novel Atopobium isolate from the human vagina: description of Atopobium vaginae sp. novInt J Syst BacteriolYear: 1999 4915737610555338|
|22.||Collins MD,Wallbanks S. Comparative sequence analysis of the 16s rRNA genes of Lactobacillus minutus, Lactobacillus rimae and Streptococcus parvulus: proposal for the creation of a new genus AtopobiumFEMS Microbiol LettYear: 199274235401382033|
|23.||Stackebrandt E,Ludwig W. The importance of using outgroup reference organisms in phylogenetic studies: the Atopobium case Syst Appl MicrobiolYear: 19941173943|
|24.||Verhelst R,Vestraelen H,Claeys G,Verschraegen G,Delanghe J,Van Simaey L,De Ganck C,Temmerman M,Vaneechoutte M. Cloning of 16S rRNA genes amplified from normal and disturbed vaginal microflora suggests a strong association between Atopobium vaginae, Gardnerella vaginalis and bacterial vaginosis BMC MicrobiolYear: 200441615102329|
|25.||Burton JP,Devillard E,Cadieux PA,Hammond JA,Reid G. Detection of Atopobium vaginae in postmenopausal women: cultivation-independent methods warrants further investigationJ Clin Microbiol Year: 20044218293115071062|
|26.||Burton JP,Chilcott CN,Al-Qumber M,Brooks HJ,Wilson D,Tagg JR,Devenish C. A preliminary survey of Atopobium vaginae in women attending the Dunedin gynaecology out-patients clinic: is the contribution of the hard-to-culture microbiota overlooked in gynaecological disorders?Aust N Z J Obstet GynaecolYear: 200545 450216171487|
|27.||Ferris MJ,Masztal A,Martin DH. Use of species-directed 16S rRNA gene PCR primers for detection of Atopobium vaginae in patients with bacterial vaginosisJ Clin MicrobiolYear: 2004425892415583334|
|28.||Vestraelen H,Verhelst R,Claeys G,Temmerman M,Vaneechoutte M. Culture-independent analysis of vaginal microflora: the unrecognized association of Atopobium vaginae with bacterial vaginosis Am J Obstet GynecolYear: 20041911130215507931|
|29.||Workwoski KA,Berman S. Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines 2010Recommandation and ReportsYear: 2010Month: 12 Day: 17 59RR121110|
|30.||Togni G,Battini V,Bulgheroni A,Mailland F,Caserini M,Mendling W. In vitro activity of nifuratel on vaginal bacteria: could it be a good candidate for the treatment of bacterial vaginosis? Antimicrob Agents ChemotherYear: 2011552490221321147|
|31.||Hay P. Recurrent bacterial vaginosisCurrent Opinion in infectious diseasesYear: 200922828619532085|
|32.||Dickey LJ,Nailor MD,Sobel JD. Guidelines for the treatment of bacterial vaginosis: focus on tinidazoleTher Clin Risk Management Year: 200954859|
|33.||Ferris DG,Litaker MS,Woodward L,Mathis D,Hendrich J. Treatment of bacterial vaginosis: a comparison of oral metronidazole, metronidazole vaginal gel and clindamycin vaginal creamJ Fam PractYear: 19954144397595261|
|34.||Larsson PG,Forsum U. Bacterial vaginosis: a disturbed bacterial flora and treatment enigmaAPMISYear: 20051133051616011656|
|35.||Fredricks DN,Fiedler TL,Thomas KK,Mitchell CM,Marrazzo JM. Changes in vaginal bacterial concentrations with intravaginal metronidazole therapy for bacterial vaginosis as assessed by quantitative PCRJ Clin MicrobiolYear: 2009477212619144794|
|36.||Beigi RH,Austin MN,Meyn LA,Krohn MA,Hillier SL. Antimicrobial resistance associated with the treatment of bacterial vaginosis Am J Obstet GynecolYear: 20041911124915507930|
|37.||De Backer E,Verhelst R,Vestraelen H,et al. Antibiotic susceptibility of Atopobium vaginaeBMC Infect DisYear: 200665116542416|
|38.||Goldstein EJ,Citron DM,Merriam CV,Warren YA,Tyrrell KL,Fernandez HT. In vitro activities of Garenoxacin (BMS 284756) against 108 clinical isolates of Gardnerella vaginalisAntimicrob Agents ChemotherYear: 2002463995612435709|
|39.||Nagaraja P. Antibiotic resistance of Gardnerella vaginalis in recurrent bacterial vaginosisIndian J Med MicrobiolYear: 200826155718445953|
|40.||Hillier SL,Homes KK. Homes KK,Sparling PF,Mardh PA,Lemon SM,Stamm WE,Piot P,WasserheitBacterial vaginosis, in Sexually Transmitted DiseasesYear: 1999New YorkMcGraw-Hill56386|
|41.||Geissdorfer W,Bohmer C,Pelz K,Schoerner C,Frobenius W,Bogdan C. Tubo-ovarian abscess caused by Atopobium vaginae following transvaginal oocyte recoveryJ Clin MicrobiolYear: 200341 27889012791933|
Keywords: Keywords Antibiotic resistance, Atopobium vaginae, bacterial vaginosis, nifuratel, review..
Previous Document: The clinical pharmacology of short acting analgo-sedatives in neonates.
Next Document: From laparoscopic assisted radical vaginal hysterectomy to vaginal assisted laparoscopic radical hys...