Use of Locally Delivered Dequalinium Chloride in the Treatment of Vaginal Infections: a Review

Arch Gynecol Obstet (2016) 293:469–484 DOI 10.1007/s00404-015-3914-8

REVIEW

Use of locally delivered dequalinium chloride in the treatment of vaginal infections: a review

1 1 2 Werner Mendling • Ernst Rainer Weissenbacher • Stefan Gerber • 3 3 Valdas Prasauskas • Philipp Grob

Received: 30 June 2015 / Accepted: 12 October 2015 / Published online: 27 October 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract the available and relevant pharmacological and clinical data for Background Vaginal infections are responsible for a large the therapy of vaginal infections with vaginal DQC and pro- proportion of gynaecological outpatient visits. Those are vides the rationale for its use in daily gynaecologic practice. bacterial vaginosis (BV), vulvovaginal candidosis (VVC), aerobic vaginitis (AV) associated with aerobic bacteria, Keywords Dequalinium chloride Á Vaginal infections Á and mixed infections. Usual treatments show similar Vulvovaginal candidosis Á Aerobic vaginitis Á Vaginal acceptable short-term efficacy, but frequent recurrences tablets and increasing microbial resistance are unsolved issues. Furthermore, vaginal infections are associated with a variety of serious adverse outcomes in pregnancy and Introduction generally have a major impact on quality of life. Identi- fying the correct therapy can be challenging for the clini- The human vaginal microbiome is mainly dominated by cian, particularly in mixed infections. lactobacilli, depending on the ethnic background of Findings Dequalinium chloride (DQC) is an anti-micro- women, and consists of probably more than 250 other bial antiseptic agent with a broad bactericidal and fungicidal different species of bacteria in lower quantities [1, 2]. activity. Systemic absorption after vaginal application of Although this interactive vaginal ecosystem and its dis- DQC is very low and systemic effects negligible. Vaginal turbances are not yet fully understood, it is obvious, that it DQC (FluomizinÒvaginal tablets) has been shown to have can change to dysbiosis (disturbed homeostasis or unbal- equal clinical efficacy as clindamycin in the treatment of BV. anced ecosystem) and demonstrate specific ‘metabolic Its broad antimicrobial activity makes it appropriate for the signatures’ [3] or can be affected by pathogens causing treatment of mixed vaginal infections and in case of uncer- infectious diseases. Moreover each woman possess her own tain diagnosis. Moreover, resistance of pathogens is unlikely and personal vaginal flora; so any management must con- due to its multiple mode of action, and vaginal DQC provides sider this individual point of view. Disturbed or abnormal also a reduced risk for post-treatment vaginal infections. vaginal flora is divided into vaginal infections which are Conclusions Vaginal DQC (10 mg) as 6-day therapy offers localised and affect mainly to the vagina, nevertheless a safe and effective option for empiric therapy of different sometimes disease can spread further to other organs. Most vaginal infections in daily practice. This review summarizes sexually transmitted infections (STI) belong to this latter class of diseases. They do often not affect the vagina itself, but the cervix or the urethra (Chlamydia trachomatis, & Werner Mendling [email protected] Neisseria gonorrhoeae), while Trichomonas vaginalis involves both urogenital parts. Vaginal dysbiosis or infec- 1 German Center for Infections in Gynecology and Obstetrics, tions are usually characterised by an abnormal vaginal Wuppertal, Germany discharge and other vaginal signs and symptoms. They can 2 Hospital Daler, Fribourg, Switzerland be differentiated into vaginosis, which does not show 3 Medinova AG, Zurich, Switzerland inflammation signs, and vaginitis (usually candidosis or 123 470 Arch Gynecol Obstet (2016) 293:469–484 aerobic infection), which leads to inflammation. Vaginal that predispose an individual to recurrent infection. Main- infections and STI are responsible for a large proportion of tenance-suppressive regimens of antimicrobial agents and gynaecological outpatient visits, from 10 to 20 % of con- the repetitive application of hydrogen peroxide-producing sultations, and are typical in woman of childbearing age. lactobacilli to restore and support the healthy vaginal flora Further important issues with these vaginal infections are should be considered as treatment options to prevent the very high rate of recurrences and a variety of associated recurrences [5, 7, 17–22]. serious adverse outcomes in pregnancy. Finally, they have The choice of an anti-infective compound depends on a major impact on the quality of life and driving these the type of infection: According to various guidelines, women exhausted. 5-nitroimidazoles (e.g., metronidazole, tinidazole) are used Although the knowledge about the bacteria- or yeast- for the treatment of BV and TV. VVC is treated with orally host interactions has increased, there are still open ques- or locally administered imidazoles or triazoles (e.g., tions regarding the interactions of vaginal lactobacilli and clotrimazole, miconazole, and fluconazole), polyenes or pathogens or the role of biofilm [4–6]. It seems that the ciclopiroxolamine. Thus depending on the pathogens local immunity by the vaginal mucosa also plays an involved, different antimicrobial agents (antibiotics, important role. The differential diagnosis of the vaginal antiseptics, antimycotics, etc.) are used as first line therapy, infections is presented in Table 1, Vaginal infections are and controlled trials have shown cure rates of 70–80 % highly recurrent and are not only adversely affecting after 4 weeks of treatment [5, 7, 8, 18, 21–31]. quality of life but are also associated with a variety of For the treatment of BV, anti-infectives with activity serious obstetrical and gynaecological complications (pre- against anaerobes are indicated, and routine treatment of term birth, salpingitis, and many others) [5, 7–9]. Three sexual partners is usually not recommended [32, 33]. main vaginal infections are well defined: (1) bacterial Currently, metronidazole and clindamycin taken orally or vaginosis (BV), (2) vulvovaginal candidosis (VVC), and applied vaginally are the mainstays of BV therapy. They (3) trichomoniasis/Trichomonas vaginitis (TV). Addition- have different spectra of antimicrobial activity but equiv- ally, there are other vaginal infections which have not yet alent efficacy with regard to short-term and long-term cure been completely characterised and recognised. Especially rates [15, 23, 34–36]. Oral therapy with metronidazole is the ‘intermediate flora’ (based on Nugent score 4–6) and usually preferred over vaginal application according to the the not well defined ‘mixed flora’ or ‘abnormal vaginal various guidelines; however, due to its metabolism in the flora’ (AVF) could possibly play a bigger role in the liver it is associated with frequent gastro-intestinal side development of preterm birth than expected before [10]. effects [27, 35, 37–39]. Clindamycin is usually recom- Moreover, aerobic bacteria are also involved in vaginal mended in the form of a vaginal cream. There are several infections but their role is not yet understood. Based on this disadvantages associated with these two therapies [15]: a knowledge a fourth, still poorly characterised type of significant proportion of patients do not achieve an ade- vaginal infections has been defined: aerobic vaginitis (AV) quate response [27, 40], recurrence of BV frequently [11], which is probably the same entity as desquamative occurs [23, 27, 38], drug resistance may develop [4, 8, 41– inflammatory vaginitis (DIV), where severe inflammation 43], and there is a risk of post-treatment candidosis [38, is observed and complains are more intense [12, 13]. 44–46]. Additionally, mixed vaginitis (MV) and co-infection with VVC is usually treated with topical azoles that are avail- coexistence of BV, VVC, and TV, is possible [14], and thus able in a variety of formulations [7, 8, 22, 47]. No evidence diagnosis and treatment of vaginal infections is not always exists to suggest that one azole type or formulation results in easy. This situation can be very challenging for the clini- better cure rates. The cure rates for topical azoles are cian who has to choose the effective treatment according to approximately 80 % [48]. Oral azole formulations also this diagnosis. achieve comparable cure rates; however, they have the Treatment options for vaginal infections remain limited potential of systemic toxicity, sometimes restricting its use. and the outcome is often unsatisfactory, particularly [7, 8, 22]. Particularly considering recurrence of Candida regarding the frequent recurrences [15, 16]. This situation infection and azole resistance, treatment with non-azole is especially frustrating for women but also for the physi- agents has its place in practice and might be even more cian. The main treatment objectives are the alleviation of important in the future [8, 21, 25, 49]. the symptoms, the elimination of pathogens, and eventually The basis of TV therapy remains the 5-nitroimidazole the recovery from disturbed to a healthy lactobacilli- group of drugs—metronidazole and tinidazole [7, 8, 49]. dominated vaginal flora. Antibiotics exhibit a specific Oral therapy is necessary, because infection of the urethra antimicrobial action which renders them effective drugs for and periurethral glands provides sources for endogenous the treatment of infections. To achieve better long-term relapses. Cure rates of up to 95 % may be achieved when results, every effort should be made to eliminate factors sexual partners are treated concomitantly [7, 8, 49]. 123 Arch Gynecol Obstet (2016) 293:469–484 471

Table 1 Differential diagnosis of vaginal infections [11, 49, 109] Bacterial vaginosis Aerobic vaginitis Mixed/disturbed Vulvovaginal candidosis Trichomoniasis vaginal ﬂora

Involved Anaerobic bacteria e.g. Aerobic bacteria, Anaerobic and/or C. albicans (80–90 %) Trichomonas pathogens Gardnerella (facultative e.g. aerobic bacteria C. glabrata (2–5 %) vaginalis anaerobic), Atopobium, Staphylococci, and/or Candida C. krusei (1-2 %) Prevotella, Mobiluncus, etc. Streptococci, etc. Symptoms Greyish-white, thin, Persistent Increased persistent Itching, burning, Foamy, thin, green homogeneous discharge, yellow- yellowish thin dyspareunia, yellowish yellowish fishy smell greenish discharge, burning white ‘‘cottage cheese’’ discharge, dysuria, discharge, or itching possible discharge itching, burning burning Signs No redness, no inflammation Redness, Redness and Redness, inflammation Irregular spotted inflammation inflammation redness, local possible bleeding especially after intercourse pH [4.5 [5.0 [4.5 \4.5 C5.0 Amine Positive Negative Possible useful Negative Possible (KOH)-test Microscopy Lactobacilli Lactobacilli reduced/not Lactobacilli Lactobacilli reduced/ Lactobacilli normal or Lactobacilli normal present reduced/not not present reduced or reduced present Clue cells Clue cells present No clue cells No/positive clue cells No clue cells No clue cells Leucocytes Leucocytes normal Leucocytes Leucocytes possibly Leucocytes normal or Leucocytes strongly increased increased increased increased, toxic Pathogens Adherent gram-negative rods, Coliform Various Candida pseudo hyphae Trichomonas etc. bacteria, and/or blastospores vaginalis B-streptococci Culture Not suitable for diagnosis, low Limited value Limited value Useful, particularly for Possible, specific specificity recurrent VVC Diagnosis 3 of 4 Amsel criteria positive Symptoms and Presence of multiple Symptoms and signs, Symptoms and or Nugent score 7–10 signs, clinical findings evidence of candida signs, evidence of microscopy or T. vaginalis AV-score Treatment Oral or vaginal antiinfective, Broad spectrum Broad spectrum Oral or local antimycotic, Oral antiinfectives e.g., metronidazole, antiinfective, antiinfective, e.g., e.g., clotrimazole, (e.g., clindamycin, and e.g., dequalinium fluconazole, nystatin, metronidazole), dequalinium chloride dequalinium chloride dequalinium chloride partner treatment Restoration of the vaginal chloride Restoration of the Restoration of the vaginal Restoration of the ecosystem Corticosteroids vaginal ecosystem ecosystem vaginal ecosystem Restoration of the vaginal ecosystem

Standard treatment for other vaginal infections has not [14] drug substances with broad spectrum of antimicrobial been established yet. For AV, clindamycin or antibacterial activity are used or a strategy of two-step therapy might be agents with activity against aerobic gram-positive and - proposed. negative bacteria, such as kanamycin [11, 26, 50, 51] but Increasing resistance against metronidazole and clin- also corticosteroids [12] are suggested. Alternatively, damycin has been reported by several investigators [40, 42, products containing oestrogen alone or in combination with 43, 53]. So far, true acquired antimicrobial resistance lactobacilli have been used [52]. For the treatment of MV occurring in vaginal infections has not been observed as a

123 472 Arch Gynecol Obstet (2016) 293:469–484 major problem in clinical practice [27, 54]. Nevertheless, 1. Its effects on bacterial cell permeability are based on misuse of the over-the-counter (OTC) antimycotics, as well (1) the adsorption on the microorganism’s cell surface as widespread use of systemic oral azoles, could result in and diffusion through the cell wall, and (2) binding to spread of azole-resistant Candida albicans, and even more the cytoplasmic membrane with subsequent formation likely it could lead to an increase in non-albicans Candida of complexes and protein precipitation [65, 66]. The species with intrinsic azole resistance [54, 55]. cell membrane might be lysed (depending on the In the case of any vaginal infection, the healthy vaginal concentration), resulting in perturbed osmotic microflora is usually disturbed, i.e., the number of lacto- exchange. bacilli is dramatically reduced or less beneficial lactobacilli 2. The effects on microbial proteins and metabolic such as Lactobacillus iners are dominant, resulting in reactions after diffusion through the cell wall are unstable vaginal microbiome [56–58]. Following anti-in- caused through (1) denaturation of proteins resulting in fective treatment, local therapy with beneficial probiotic inhibition of bacterial cell metabolism, (2) disruption lactobacilli is recommended to support long-term restora- of bacterial energy production through inhibition of tion of vaginal flora [59, 60]. Repetitive lactobacilli therapy glucose metabolism and inhibition of mitochondrial also has been proposed to normalise the vaginal ecosystem ATP synthesis via inhibition of bacterial F1-ATPase, to prevent the recurrences of vaginal infections, especially and (3) termination of protein synthesis at the level of BV [59, 61, 62]. ribosomes [65, 66, 73]. Furthermore effects on bacte- Although antibiotics are selective and effective anti-in- rial nucleic acids occur such as (1) precipitation of fectives, it is nevertheless still necessary and desirable to cytoplasmic material with nucleic acids being the most broaden the therapeutic possibilities [1, 15]. As alternative sensitive, and (2) binding to DNA (in vitro) [63, 65, therapy broad spectrum antimicrobial agents, such as 66]. dequalinium chloride (DQC), are used to treat vaginal Disruption of cell permeability and subsequent loss of infections. Typical representatives are phenyl derivates enzymatic activity is regarded as the primary cause of (e.g., chlorhexidine, hexetidine), acids (e.g., salicylic acid), bacterial cell death after contact with surface-active com- halogens (e.g., povidone-iodine), and quaternary ammo- pounds [65]. The enzymatic inactivation initially might be nium compounds (e.g., DQC). Less specific antimicrobial reversible but becomes irreversible after a longer contact agents have the advantage that (1) resistance of pathogenic time between DQC and the bacteria. Protein denaturation microorganisms is not to be expected due to its multiple and inhibition of metabolic reactions are only obtained at mechanism of action [63–66], (2) they can also be used for doses above the clinical use of quaternary ammonium mixed vaginal infections because of their broad antimi- compounds, and are therefore less relevant for their crobial spectrum, as well as additionally (3) for pre- and antimicrobial action. post-operative prophylaxis. The antimicrobial activity of DQC has been investigated The goal of the current article on DQC is to review the and demonstrated over the past decades by several inves- pharmacology and clinical evidence to better understand tigators [67, 69, 70, 72, 74–80]. An overview of the in vitro this substance and to provide the rationale for its use in antimicrobial activity of DQC is shown in Table 2, DQC daily clinical practice for the treatment of vaginal has a broad antimicrobial activity against all relevant infections. vaginal pathogens. The bactericidal and fungicidal effect of DQC has been demonstrated to occur within 30–60 min [67]. Della Casa and colleagues demonstrated the in vitro Pharmacology antimicrobial activity of DQC against different pathogens that are relevant for vaginal infections, including anaerobic Dequalinium chloride (DQC)—1,10-(decane-1,10-diyl) bis bacteria (Gardnerella vaginalis, Bacteroides spp., Pep- (4-amino-2-methylquinolinium) dichloride—is a bis-qua- tostreptococcus spp., etc.), aerobic bacteria (staphylococci, ternary ammonium compound with a broad spectrum streptococci, Escherichia coli, etc.), Candida species (C. against gram-positive and -negative bacteria, yeasts, and albicans, C. glabrata, etc.) and Trichomonas vaginalis protozoa [67–70] (Fig. 1). [69]. The antimicrobial activity of DQC against Candida The antimicrobial activity of DQC and quaternary spp. is comparable with clotrimazole and ciclopiroxo- ammonium salts in general, is primarily based on their lamine [69]. A recent in vitro study has also demonstrated a ability to increase cell permeability with subsequent loss of high susceptibility of Atopobium vaginae to DQC, and enzyme activity [66, 70–72]; the substance exhibits a rapid confirmed that DQC acts bactericidal [80]. bactericidal and fungicidal action [67]. No development of resistance of micro-organisms to In detail the mechanism of action of DQC is based on DQC has been reported in laboratory studies or clinical the following mechanisms (Fig. 2): 123 Arch Gynecol Obstet (2016) 293:469–484 473

Fig. 1 Structure of dequalinium chloride (DQC)

Fig. 2 Mechanism of action of dequalinium chloride (DQC)

trials. Resistance of pathogens is unlikely due to the mul- 0.625 % of the administered 5 times higher dose/kg, thus tiple mode of action of DQC. In fact, multidrug resistance maximum blood levels only in the pg/ml could be expected to single quaternary cationic anti-infectives is associated after vaginal application of DQC in humans. This is con- rather with hypersensitivity to compounds containing two sistent with ﬁndings in animal toxicology studies, indicat- quaternary cations, including DQC [81]. ing that DQC is absorbed to an extremely small degree For human subjects, published information on quater- (\0.1 %) after oral application [74]. nary ammonium compounds conﬁrms that the blood levels No reproductive toxicity studies have been conducted in after oral administration (10–40 mg) are generally low animals because of the anticipated low systemic exposure [82–87]. It is expected that absorption is even lower after to DQC after vaginal administration. Animal studies with vaginal application [85], supported by the fact that vaginal other quaternary ammonium compounds have not shown application of DQC is very rarely associated with systemic embryo-foetal toxicity at clinically relevant doses [84]. adverse events as demonstrated in clinical studies. In a Preclinical data indicate that DQC is absorbed only to a local repeated dose vaginal tolerability study in rabbits, very small degree after vaginal application, i.e., systemic where daily doses per kg were 2.5–5 times higher than in exposure is negligible [74]. clinical use, no DQC was detected in the blood. Absorption DQC 10 mg vaginal tablet (FluomizinÒ) has been of DQC in rabbits after vaginal application was below developed as a directly compressed vaginal tablet to ensure

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Table 2 In vitro antimicrobial Gram stain MICa (lg/ml) MICb (lg/ml) activity of dequalinium chloride range 90 (DQC) [66, 67, 69, 74–80] Anaerobic bacteria Gardnerella vaginalis -/? 2–512 256 Atopobium vaginae -/? \0.0625–0.5 0.5 Bacteroides spp./Prevotella spp./Porphyromonas spp. – 8–512 256; 512 Peptostreptococci 1 1–32 Fusobacteria – 32–64 Aerobic gram-positive bacteria Enterococcus faecalis 1 0.2–64 64 Lactobacillus spp. 1 0.5–8 4 Staphylococcus aureus 1 0.2–8 1.28; 8 Streptococcus agalactiae (group B streptococci) 1 2–64 8; 32 Streptococcus pyogenes (group A streptococci) 1 0.25–20 2 Aerobic gram-negative bacteria Enterobacter spp. – 3.1–400 Escherichia coli – 1–400 128 Klebsiella spp. – 3.1–400 Pseudomonas spp. – 5–400 Serratia spp. – 3.1–400 Proteus spp. – 20–[1024 Fungi Candida tropicalis 0.2–50 Candida albicans 0.2–50 1; 8 Candida glabrata 0.2–256 1; 256 Candida krusei 128 128 Aspergillus spp. 1.6–6.3 Trichophyton spp. 1.56–3.12 Protozoa Trichomonas vaginalis 28.8–400 57.6

a MICrange: minimum and maximum MIC values for certain species b MIC90: MIC value at which 90 % of the strains of this species were inhibited fast disintegration of the tablet and rapid dissolution of the Clinical studies active substance. As soon as the vaginal tablet comes into contact with the vaginal secretion, the tablet begins to Local treatment of vaginal infections with DQC is well disintegrate and DQC is released. After dissolution of the established. Various clinical studies published over the last DQC 10 mg tablet in an estimated 2.5–5 ml of vaginal 4 decades demonstrate its good clinical efficacy in different fluid, the DQC concentration is estimated at vaginal formulations [26, 28, 32, 34, 88–106]. 2000–4000 lg/ml, assuming negligible absorption. This The dose tested for the treatment of vaginal infections concentration is four to eightfold higher than the minimal ranged from 10 to 50 mg. The immediate release prepa- inhibitory concentration (MIC) of the least susceptible rations were used with a strength of 10 and 20 mg DQC, isolate (MIC = 512 lg/ml) [66]. An in vivo anti-infective whereas controlled release preparation contained 20 or effect is generally obtained if the concentration of the 50 mg of DQC. Treatment duration was usually 3–10 days. active substance at the site of action is 2–4 times higher The efficacy over the entire dose range was similar and no than the MIC for 20 min up to 2 h [69]. difference in tolerability was described [26, 28, 32, 34, 88– The broad spectrum antimicrobial activity covering all 106]. The medicinal products containing DQC which were relevant pathogens for vaginal infections and the negli- tested for vaginal administration in clinical studies are gible systemic absorption are the key factors of DQC to briefly summarised in Table 3. make it suitable for the treatment of most vaginal Within clinical studies, more than 3000 women with infections. vaginal infections of different aetiology have been treated

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Table 3 Medicinal products containing dequalinium chloride (DQC) reported in the treatment of vaginal infections Medicinal product Formulation References

DequadinÒ Vaginal pessary 10 mg [88, 95, 99] DequavagynÒ Ovule 50 mg; controlled release for 8–10 days [34, 96] DequavagynÒ Cream 20 mg/10 g cream; controlled release for 8–10 days [34, 91–94, 96, 97, 100] Oestro-DequavagynÒ Cream 20 mg/10 g cream; controlled release for 8–10 days [93, 98] ?0.15 mg estriol/10 g cream Oestro-DequavagynÒ Cream 20 mg/10 g cream; controlled release for 8–10 days [93] ?2 mg Estriol/10 g cream GykenÒ Ovule 20 mg [28] ErioseptÒ Vaginal foam 100 mg/100 g [101] FluomizinÒ 10 mg vaginal tablet [26, 32]

with vaginal DQC (Table 4). Clinical studies have been more than 20 % clue cells criterion: to be cured of BV the mainly carried out in the treatment of the following vaginal patient could have clue cells present but less than 20 %. At infections: (1) BV, (2) VVC, (3) less characterised aerobic week 1, clinical cure rates were 81.5 % in women treated and mixed vaginal co-/infections (‘fluor vaginalis’). with 10 mg DQC and 78.4 % in clindamycin-treated women, the difference was not statistically significant. The Treatment of bacterial vaginosis (BV) treatment of BV with a 6-day course of 10 mg DQC vaginal tablets had therefore equal efficacy as a 7-day Two recent high quality clinical studies (Weissenbacher course of clindamycin vaginal cream. At week 4, the et al. and Petersen et al.) have investigated efficacy and overall clinical cure rates observed were 79.5 % with safety of 10 mg DQC vaginal tablets for treatment of BV— 10 mg DQC and 77.6 % with clindamycin, demonstrating a total of 212 women have been treated [26, 32]. that the efficacy of DQC was as good as clindamycin DQC have been used for a very long time and the first (statistically significant) also at long-term follow-up. Most reference was from 1959. There was no consensus of the Amsel criteria were fairly comparable with slight, but diagnosis of BV at that time. Hence, many older clinical clinically not relevant, differences between the groups. The data should be evaluated with scientific precaution. Nev- total failure rates, including non-responders and BV ertheless, additionally some older studies could also pro- recurrences, for the two groups were also comparable. The vide some supportive data on clinical efficacy of DQC in number of women with positive cultures of Candida spp. the treatment of vaginal infections which currently could (‘colonisation’) at week 4 was slightly higher in the clin- be described as BV. Within these older clinical studies damycin group (14.6 %) than in the DQC group (9.3 %), (including some unpublished data) a total of 577 women however, due to small figures statistically not significant. with more or less well diagnosed BV-like syndromes have Consistent with these results, symptomatic VVC at second been treated with various vaginal DQC preparations [26, follow-up was half as common with DQC (2.7 %) than 28, 32, 104, 107]. with clindamycin (5.8 %). No serious adverse drug reac- In a recently published multicentre, controlled study tions (ADRs) were observed. The proportion of women Weissenbacher and colleagues compared the efficacy of reporting ADRs was 17.8 % in the DQC group and 20.3 % DQC 10 mg vaginal tablets (FluomizinÒ) once daily for in the clindamycin group. The most frequently reported 6 days to clindamycin vaginal cream 2 % for 7 days in the reactions in both groups were vaginal discharge followed treatment of BV [32]. To qualify for inclusion, women had by vulvovaginal pruritus. to be diagnosed with BV, for which all 4 Amsel criteria had Petersen et al. [26] in a controlled, randomised, double- to be present. Follow-up visits were performed at 1 week blind, multicentric clinical study compared the efficacy and and at 4 weeks after the treatment. A total of 321 women safety of 10 mg DQC vaginal tablets (FluomizinÒ) and were randomised to receive either 10 mg DQC (n = 164) 200 mg vaginal povidone iodine in a parallel-group design or clindamycin (n = 157). The primary efficacy outcome [26]. A total of 180 women with vaginal infections of was clinical cure, where clinical cure was defined as the varying aetiology participated in this study. Women were absence of clue cells and a negative result for at least 2 randomly allocated to one of the two treatment groups other Amsel criteria. Weissenbacher et al. have used the (DQC—121 and povidone iodine—59) and were treated

123 476 123 Table 4 Overview of clinical studies with dequalinium chloride (DQC) Publication and design Subjects and indications Medication Efﬁcacy Safety

Monopreparation Weissenbacher, 2012 321: BV—321 FluomizinÒ vaginal tablets vs. At week 1, cure rates were 81.5 % with 10 mg DQC and Only ADRs - discharge [32] clindamycin 2 % cream vaginal 78.4 % in clindamycin group. 10 mg DQC vaginal followed by tablets had equal efficacy as a clindamycin vaginal vulvovaginal pruritus Controlled, comparative 6 days cream. At week 4, cure rates were 79.5 % with 10 mg DQC and 77.6 % with clindamycin, demonstrating that the efficacy of DQC was not inferior to that of clindamycin (significant). Radzinsky et al., 2011 622: BV—409; ‘nonspecific FluomizinÒ vaginal tablets 6 days vs. FluomizinÒ group – cure 77.8 % (best dynamics observed Not assessed [107] vaginitis’—213 standard anti-infective treatment for disappearance of the ‘clue cells’); standard antiinfective treatment – cure 77.1 % (average). Comparative, two-stage (afterwards GynoflorÒ restoration) therapy Dankovich and 45: Abnormal vaginal flora—45 FluomizinÒ vaginal tablets 6 days Disturbed vaginal flora in 44 women became healthy, only None Gopchuk, 2006 [102] 1/45 patient had complication after surgery. Open, pre-operative prophylaxis Grishchenko et al., 2006 66 (pregnant): BV—66 FluomizinÒ (34) vs. povidone-iodide Sanitation of vagina, demonstrated favourable pregnancy None [104] vaginal conditions and perinatal outcomes. Open Grishchenko et al. 2006 76: Mixed infection—76 FluomizinÒ (45) vs. chlorhexidine Cure rate after the treatment with FluomizinÒ—96.7 %, Local ADRs—5 [105] bigluconate vaginal with chlorhexidine bigluconate—66.0 %. patients; discontinued therapy—2 Demina et al., 2005 60 (pregnant): BV and FluomizinÒ (32) vs. povidone iodine Vaginal ecosystem recovery—in all pregnant women of None [103] ‘opportunistic flora vaginitis’— vaginal group I after one treatment, and vaginal clearance of Open 60 degrees I and II was seen in 91.7 %. No Candida albicans after FluomizinÒ. Petersen, 2002 [26] 121: BV—48; VVC—23; TV— FluomizinÒ vaginal tablets vs. povidone Symptoms decreased in the FluomycinÒ group from 5.13 5.8 % reported a local Controlled 5; other—45 iodine vaginal to 1.33. BV: 96 % and 82 % of women were diagnosed ADRs BV-negative after therapy at short- and long-term follow- 293:469–484 (2016) Obstet Gynecol Arch up, respectively. VVC: symptoms decreased from 6.5 at to 1.1. Flour vaginalis: symptoms decreased from 5.0 to 1.3. Schmidt, 2000 446 (60 pregnant) FluomycinÒ N (10 mg DQC) vaginal 303 patients (67.9 %) at entry showed 3 to 4 symptoms, None (unpublished) BV—126; TV—10; VVC—97; tablets, daily 6 days whereas at control only 42 patients (9.4 %). A distinct Open, drug utilisation flour vaginalis—213 improvement in all documented clinical symptoms. trial Strecker, 1993 [28] 388 (mixed group is included GykenÒ ovula twice (3 or 4 days Negative microscopy (cure): BV—115 (31 %); VVC—86 1 case of enhanced Open twice) interval) (76 %) sleepiness BV—375; VVC—113 rhGnclOse 21)293:469–484 (2016) Obstet Gynecol Arch Table 4 continued Publication and design Subjects and indications Medication Efficacy Safety

Warnecke, 1976 [101] 100 ErioseptÒ 0.1 % vaginal spray once Negative microscopy (cure): Fluor vaginalis—4 (57 %); None Open fluor vaginalis—7; ‘non-infective daily ‘non-infective colpitis’—67 (84 %); other—10 (77 %) colpitis’—80; other—13 3 days (84), 6 days (11) Fauner, 1974 [91] 55 (pregnant) DequavagynÒ depot once, eventual Negative microscopy (cure): VVC first therapy—46 None Open VVC: 55 repetition after 1 week (84 %), second therapy—8 (14 %) Kucera, 1973 [93] 150: Bacterial fluor vaginalis— DequavagynÒ depot alone or with Negative microscopy (cure, DequavagynÒ depot alone): Not assessed Active-controlled 116; VVC—15; TV—14; 0.0015 % estriol, or with 0.02 % flour vaginalis—30 (79 %), VVC—3 (75 %), TV—4 mixed infection—5 estriol (Oestro-DequavagynÒ) twice, (67 %), mixed infection—0 (0 %) repetition after 1 week Kolbe, 1972 [92] 124: Bacterial fluor vaginalis— DequavagynÒ depot once, eventual Cure (examination not specified): Bacterial fluor 1 case of generalised Open 42; VVC—50; TV—27; repetition after 10 days vaginalis—42(100 %), VVC—47 (94 %). TV— pruritus TV ? VVC—5 26(96 %), TV ?VVC—3 (60 %) Mu¨hlbauer, 1972 [97] 134: Bacterial fluor vaginalis— DequavagynÒ depot once (continuous Negative microscopy (cure): Bacterial fluor vaginalis—33 None Open 44; VVC—78; TV—12 DQC release over 8-10 days) (76 %), VVC 56 (72 %), TV—2 (24 %) Tatra, 1972 [100] 311: Bacterial fluor vaginalis— DequavagynÒ depot once, eventual Negative microscopy (cure): Bacterial fluor vaginalis— 1 case of generalised Open 180; VVC—69; TV—48; repetition after 10 days 147 (82 %), VVC—53 (77 %), TV—8 (30 %), pruritus TV ? VVC—13 TV ? VVC 0 (0 %) Lange, 1971 [94] 82: Bacterial fluor vaginalis—8; DequavagynÒ depot once, eventual Negative microscopy (cure): Bacterial fluor vaginalis—8 1 case of purulent Open VVC—38; TV—36 repetition after 10 days (73 %), VVC—38 (76 %), TV - 36 (92 %) discharge Martin & Martin, 1971; 200 (several indications DequavagynÒ depot once, eventual Negative microscopy (cure): Bacterial fluor vaginalis—9 1 case of pruritus Martin, 1971 [34, 96] possible): Bacterial fluor repetition after 10 days (66 %), VVC—117 (68 %), TV—2 (50 %), ‘super- (allergy) vaginalis—44; VVC—173; infection’—19 (90 %) Open TV—4; ‘super-infection’—21 Atlante, 1959 [88] 60 (4 mixed): VVC—2; TV—60 DequadinÒ pessary twice daily Negative microscopy (cure): VVC—4 (67 %), TV—54 None Open 5–6 days, repeated after menstruation (90 %) Levinson, 1959 [95] 43: TV—43 DequadinÒ pessary twice daily 4 weeks Negative microscopy (cure after 10 days): TV—17 (40 %) Not assessed Open Roddie, 1958 [99] 70: Bacterial fluor vaginalis—30; DequadinÒ pessary twice daily 2 weeks Symptoms after 2 weeks (absent/improved): bacterial fluor None Open VVC—4; TV—36 vaginalis—16 (59 %)/4 (15 %), VVC—2 (67 %)/1 (33 %), TV—1 (3 %)/5 (14 %) Combination(s) Rippmann, 1974 [98] 106: VVC—26; TV—31; mixed Oestro-DequavagynÒ (DQC ? 0.02 % Negative microscopy (cure): VVC—18 (69 %), TV—11 none Open infection—49 estriol) twice, repetition after 1 week (35 %), mixed infection—39 (80 %) (continuous DQC release over 8–10 days) 123 477 478 Arch Gynecol Obstet (2016) 293:469–484 once daily for 6 days. The total symptom score was defined post-treatment VVC than after clindamycin therapy. The as the overall primary efficacy parameter. Based on this drug was well tolerated; no serious ADRs were observed. parameter, the study demonstrated therapeutic equivalence of vaginal DQC and the reference preparation. In the BV Treatment of vulvovaginal candidosis (VVC) subgroup a total of 73 women were included, whereof 48 were treated with DQC. Using Amsel criteria, 96 % (after Dequalinium chloride in different vaginal formulations has 1 week) and 82 % (after 4 weeks) of patients were cured been used to treat a total of 653 women with VVC, and after 10 mg DQC therapy. The percentage of women with cure rates were reported between 70 and 90 % [26, 28, 34, positive cultures of G. vaginalis decreased clearly from 88, 91–94, 96–100]. 60 % before to 7 % after treatment. The improved micro- In a series of clinical studies [34, 91–94, 96, 97, 100], bial status was also demonstrated by the increased per- altogether 490 patients with VVC were treated with a DQC centage of women with a healthy degree of purity (pure 20 mg depot preparation. In 70–80 % of the cases, patients lactobacilli flora) in the DQC group (at entry—0 %, at were cured. Kolbe [92] reported even a cure rate of 94 %. follow-up 1 (after 1 week)—37 %, at follow-up 2 (after In 15–20 % of the cases, symptoms improved and the 4 weeks)—46 %). The normalisation of the healthy flora microscopic analysis of C. albicans showed a clearly was faster in the DQC group as compared to the reference reduced yeast load. However, in 10–25 % of the cases, group (at entry—0 %, at follow-up 1–14 %, at follow-up even a repetition of the treatment was not successful [34, 2–50 %). 93]. Also in pregnant women with VVC (n = 55), DQC Strecker and colleagues in a non-controlled clinical depot preparation led to complete cure in 84 % of the cases study tested the efficacy and local tolerability of DQC in a [91]. total of 388 women whereof 274 were diagnosed with BV Strecker et al. [28] tested a DQC 20 mg vaginal ovula at [28]. Treatment with a vaginally administered 20 mg DQC day 1 and one ovula at day 4 in women suffering from ovula (2 ovules daily in a 3 days interval) was successful in VVC with (n = 103): a positive effect—cure or improve- 70–85 % of the patients with BV with/without accompa- ment—was demonstrated on more than 90 % of cases. nying candidosis and with VVC alone. The therapeutic A DQC 20 mg and estriol combination resulted in total efficacy of was rated as good or very good by 91 % of the disappearance of C. albicans in 69 % of the microscopic patients and by 99 % of the investigators. evaluated vaginal smears and in considerable reduction of Radzinsky and co-investigators [107] presented the C. albicans in 19 % of the vaginal smears [98]. In some results of a multicentre trial using different therapy regi- studies sexual partners were also parallelly treated with a mens in 640 non-pregnant women of reproductive age with DQC vaginal cream (currently commercially not available) bacterial vaginal infections different aetiology. The trial [97, 100]: the cure rate remained at a similar range was divided into two stages: In the first stage, women 77–91 %. received anti-infective therapy against bacterial vaginosis In the earlier mentioned controlled, multicentric clinical or nonspecific vaginitis; afterwards restoration of the trial, Petersen with collaborators compared the efficacy and vaginal ecosystem was investigated with probiotic (out- safety of 10 mg DQC vaginal tablets (FluomizinÒ) and comes are not described here). In the first stage, women 200 mg vaginal povidone iodine in a parallel-group design received vaginal anti-infective treatment at the physician’s also in women with VVC [26]. Of the total of 180 women, discretion (DQC, clindamycin, chlorhexidine, povidone 35 women with VVC (23 women in DQC and 12—in iodine, or metronidazole/miconazole combination). In the povidone group) were included, where VVC was diagnosed group with BV, 409 women positive for BV according to by its typical signs and symptoms and by the presence of the Amsel criteria were included in the statistical analysis. yeasts in the wet mounts or in cultures. The clinical The efficacy of vaginal DQC based on Amsel criteria symptoms improved clearly from a total score of 6.5 at (n = 144, 77.8 %) was equivalent to the efficacy of the entry to 1.1 at the second follow-up, if treated with DQC. other anti-infective therapies (n = 281, 77.1 %). At entry, all patients (100 %) were positive for Candida Overall the clinical studies have demonstrated the spp. The percentage of positive patients decreased in the excellent efficacy of 10 mg DQC formulation FluomizinÒ DQC group clearly to 21.7 % at follow-up 1 and 15.8 % at in the treatment of BV. Clinical cure rates of 10 mg DQC follow-up 2; the corresponding values in the reference were equal to clindamycin 2 % vaginal cream, one of the group were 33.3 and 18.2 %. Global efficacy of DQC at the current ‘gold standards’ in the treatment of BV. Further- end of the study was rated as complete or considerable more, vaginal pH, number of lactobacilli and clinical improved in 84 and 89 % of cases by investigators and symptoms improved clearly during 10 mg DQC therapy; patients, respectively. DQC therapy was well tolerated with and additionally DQC demonstrated trend to less cases of no serious ADRs observed.

123 Arch Gynecol Obstet (2016) 293:469–484 479

Treatment in a so far unpublished multicentre drug publications) cured 66–76 % of the 137 patients [34, 92– utilisation trial by Schmidt has assessed the effectiveness 94, 96, 97, 108]. and tolerability of DQC 10 mg vaginal tablets (Flu- In the above-mentioned multicentre drug utilisation omizinÒ) in the treatment of ‘acute colpitis’ (vaginal trial, Schmidt in an unpublished trial have assessed the infections) under conditions of daily practice. In the VVC efficacy and safety of DQC 10 mg vaginal tablets in the group 97 women were included from 30 centres in Ger- treatment of ‘acute colpitis’ (poorly defined vaginal many. Whereas 86.6 % of the women had three or four infections). Totally 213 women were included in the sub- symptoms at the entry examination, this was the case for group of MV (bacterial mixed infection, ‘fluor vaginalis’). only 12.2 % at the control examination. The number of Whereas 62.9 % of the women had three or four symptoms women with Candida-positive culture before therapy was at the entry examination, this was the case for only 10.0 % 100 %, and decreased to 20 % after the DQC treatment. No at the follow-up examination. The number of women with ADRs were observed. positive cultures for gram-negative and gram-positive Overall, different vaginal formulations of DQC in bacteria decreased approximately by 50 %. No ADR was women with symptomatic VVC in clinical studies observed. demonstrated similar good efficacy (cure and/or improve- Petersen [26] and colleagues includes in their clinical ment rates) and safety. With the DQC 10 mg vaginal study also 73 women diagnosed with ‘fluor vaginalis’ tablets FluomizinÒ formulation a total of 120 women (in- (aerobic bacterial vaginal infection), where signs and cluding unpublished) with VVC have been treated symptoms of vaginitis and a disturbed vaginal flora were demonstrating the high clinical efficacy and tolerability present, but BV, VVC and TV were excluded. The total also for this vaginal formulation [26]. symptoms score decreased under therapy with DQC from 5.0 ± 1.9 at entry to 1.9 ± 1.5 at follow-up 1 and Treatment of less defined vaginal infections 1.3 ± 1.3 at follow-up 2. The number of leukocytes ([10 per field of view) decreased in the DQC group for 42.2 % Even though that there are concern that vaginal infections of patients at entry to 9.3 % at follow-up 1 and 8.6 % at are also caused by aerobic pathogens, there is still no follow-up 2 (4 weeks). Furthermore, the DQC therapy consensus of how ‘fluor vaginalis’ should be diagnosed and resulted in a decrease of the positive cultures for Strepto- it is difficult to compare the results from different inves- coccus ssp., Enterococcus spp., and E. coli by 36, 49, and tigators. DQC in different vaginal formulations has been 73 %, respectively, at the end of the study. also used for the treatment of the following less defined Radzinsky and colleagues [107] investigated in their vaginal infections: aerobic bacterial vaginal infections above-mentioned clinical study also the efficacy of vaginal (AV, AVF, bacterial ‘fluor vaginalis’, etc.), mixed vaginal DQC in 213 women with ‘nonspecific vulvovaginitis’ infections and co-infections, and Trichomoniasis/TV. presenting a clinical picture of an inflammatory and intense Again, the classification of mixed vaginal infections and/or leukocyte reaction ([20 leucocytes field of view in the co-infections is still purely described. These facts are not vaginal smear, magnification 400 times). The efficacy in allowing to draw sufficiently clear scientific evaluations the group of the patients receiving DQC (n = 67) was but some general conclusions probably still could be done. estimated above 76 %. The anti-infective efficacy of the broad spectrum DQC was found to be similar to that of Aerobic bacterial vaginal infections other most commonly used agents in treating vulvovaginal infections. Within 11 clinical studies, a total of 968 women that have All clinical studies consistently reported a good clinical been diagnosed with this type of vaginal infections were efficacy of DQC in the treatment of aerobic bacterial treated with vaginal DQC [26, 34, 92–94, 96, 97, 99–101, vaginal infections. This is particularly interesting as for this 103, 105, 107]. Roddie [99] has reported treatment results pathology no standard treatment has been established yet. with DQC 10 mg pessaries twice daily in 30 women with The therapy with vaginal DQC resulted in a clear reduction ‘bacterial fluor vaginalis’. Symptoms improved after of the clinical symptoms, reduction of presence of relevant 2 weeks and resumed in 70 % of the cases after 3 weeks of facultative-pathogenic microorganisms in vaginal cultures, treatment. The therapy did not lead to irritation or sensi- and was well tolerated. tisation of the vagina. Different clinical trials reported good results in treat- Mixed vaginal infections ment of ‘bacterial fluor vaginalis’ with a DQC depot preparation that, once inserted into the vagina, releases Clinical studies including women with MV are rare, only continuously DQC for 8–10 days. A single treatment with 5 published studies report the results of a total of 179 10–20 mg DQC (the precise dose is not mentioned in the women [28, 92, 93, 98, 100]. Recently Sobel et al. [14] 123 480 Arch Gynecol Obstet (2016) 293:469–484 described the MV as an infection with at least 2 pathogens with 2.4 % very low, showing the excellent local tolerance that are well defined. Additionally, it is important to of vaginally administered DQC. With the DQC 10 mg understand that ‘mixed flora’ and ‘mixed vaginal infec- vaginal tablets FluomizinÒ formulation, 1224 women have tion’ as defined by Sobel could not always be the same been treated in controlled or open clinical studies and only nosologic entity. 95 ADRs (7.8 %) were observed and none of them were After vaginal administration of an DQC ovule 20 mg at serious [26, 32, 102–106]. The majority of the ADRs in day 1 and one DQC ovule at day 4 to patients suffering clinical studies (about 90 %) were local reactions, partic- from VVC with BV co-infection (n = 11), approximately ularly vaginal discharge, vulvovaginal pruritus, and a 1/3 of the patients showed improvement of symptoms, and vaginal burning sensation. 2/3 of the patients were completely cured. These findings were confirmed by the significant reduction of the vaginal Clinical studies in pregnant women pH value below 4.5 in approximately 2/3 of the cases. Furthermore, the positive amine test turned into negative A total of 181 pregnant women have been intentionally after the treatment in 87 % of the women with BV co- treated with vaginal DQC in four clinical studies, and no infection. Therapy was not successful in only 1/10 of the adverse effects on pregnancy or on the health of the foetus/ cases [28]. new-born child (based on pH, Apgar scale, and follow-up The therapy with a combination of DQC (applied dose until 1 year) have been observed. not known) with 0.0015 % estriol (Oestro-DequavagynÒ) Fauner and Binder [91] treated 55 pregnant women with of 49 women with MV resulted in total disappearance of VVC by a DQC depot preparation that continuously the mixed flora in 80 % of the vaginal smears, and in releases active substance over 8–10 days. The tolerability considerable reduction of the mixed flora in 4 % of the and safety of the treatment was excellent and no ADRs cases [98]. were reported on pregnant women and new-born. In an unpublished drug utilisation study, 60 pregnant Trichomoniasis women were treated with DQC10 mg. The tolerability of the treatment was ‘very good’ or ‘good’ for 95 % of the Within clinical studies, a total of 329 women with TV have patients and did not differ from that of the entire group of been treated with different vaginal DQC preparations [26, patients. No ADRs were reported. Demina and colleagues 34, 88, 92–97, 99, 100]. [103] investigated the efficacy and safety of DQC vaginal In a series of clinical studies, the efficacy and tolera- tablets (FluomizinÒ) in the treatment of bacterial vaginal bility of DQC 10 mg pessaries was assessed in altogether infections during pregnancy. Sixty women in the first tri- 139 trichomoniasis cases. The average treatment lasted mester of pregnancy at risk for miscarriage and thirty 6 weeks and pessaries were applied 1–2 times per day. healthy pregnant women without complications were Overall, in 40–90 % of the cases T. vaginalis was eradi- included. The latter group of healthy pregnant women cated and patients were cured, and 10–60 % showed con- served as reference group. The women at risk for miscar- siderable improvement of symptoms [88, 95, 99]. In one riage either received FluomizinÒ vaginal tablets (group I: study, treatment was even successful in women who had n = 32) or a drug containing povidone iodine (group II: previously failed to respond in any satisfactory degree to n = 38). No ADRs were observed. In the DQC group, no any other forms of treatment including the use of pessaries case of spontaneous abortion was observed, whereas in the containing oxytetracycline which today is no first line povidone iodine group 2 spontaneous abortions were medication. However, a number of cases relapsed in a observed and any treatment by iodine during pregnancy period of 2–16 weeks after treatment end [100]. The presents a risk on the foetal iodine metabolism. treatment of trichomoniasis with DQC seems to be less Grishchenko et al. [104] treated 34 pregnant women efficient—the overall efficacy in this disease was reported (week 6–8) suffering from BV with DQC 10 mg vaginal 17–50 % [34, 96, 97]. In order to achieve complete treat- tablets (FluomizinÒ) once daily for 6 days. A control group ment success concomitant systemic medication with a tri- of 32 pregnant women was treated with povidone iodine. chomonacidal agent, for example metronidazole, should be Following this treatment, the course of the pregnancy, the used [34, 92–94, 100]. pre-natal condition of the foetus and perinatal pathology were studied. Placental dysfunction in week 16 of preg- Clinical safety nancy occurred in fewer patients treated with DQC (29.4 %) than in the control group (84.4 %). The greatest Within clinical studies, different vaginal DQC preparations differences between the groups were found in the amount have been used to treat more than 3000 women with var- of amniotic fluid and placenta maturity. Although the ious vaginal infections. The overall share of ADRs was precise role of BV in pregnancy is still debated, the authors 123 Arch Gynecol Obstet (2016) 293:469–484 481 concluded that BV is accompanied by the development of is based on an increase in cell permeability with the sub- placental dysfunction, causing high levels of pre-natal sequent loss of enzyme activity. Resistance of pathogens is foetal hypoxia and perinatal pathology, and the effective unlikely due to its multiple mode of action and has not treatment of BV with DQC in the first trimester of preg- been reported. The vaginal application of DQC results in nancy could improve the perinatal outcomes [84, 91, 103, high local concentration, but due to low absorption sys- 104]. temic exposure is negligible. In clinical studies described in the literature, medicinal products with DQC of different concentrations and vaginal Summary and conclusions formulations were used. The efficacy over the entire dose range was similar and no difference in the tolerability was Vaginal infections are a common medical problem and are described. Local treatment of vaginal infections with DQC responsible for a large proportion of gynaecological out- is well established, and many publications have demon- patient visits. These infections are associated with a variety strated its clinical efficacy in different vaginal infections. of serious adverse health outcomes, especially in pregnant Overall, more than 3000 women have been treated with women. The most common vaginal infections are BV and vaginal DQC in clinical studies for the following vaginal VVC; however AV/AVF and mixed infections are also infections: BV, VVC, AV/AVF, trichomoniasis and mixed considerably frequent. In clinical practice the correct vaginal infections. Independent of the specific DQC drug diagnosis of vaginal infections, particularly mixed infec- used, treatment of vaginal infections of bacterial and tions, is often difficult and finding an effective treatment mycotic origin has been shown to result in similarly high can be challenging for the clinician. cure rates (70–90 %). Furthermore, a recent clinical study The main treatment objectives are the alleviation of the with DQC also confirmed the comparable efficacy with symptoms, the elimination of pathogens, and eventually the clindamycin in the treatment of in BV. The DQC treatment recovery from disturbed to a healthy lactobacilli-dominated is a very interesting treatment option for BV but as there vaginal flora. Additionally high tolerability of the treatment are no long follow-up data available, it would be still is needed to increase the compliance and acceptability by reasonable to perform more clinical studies investigating the women. However, treatment options for the vaginal cure rates and at least one clinical study with longer follow- infections are limited, and the outcome is often unsatis- up (6 months). factory. Even though current treatments show accept- The safety of DQC has also been demonstrated in these able short-term efficacy with cure rates of 70–80 %, various clinical studies. No serious ADRs have been recurrent vaginal infections as well as post-treatment can- observed. The majority ([90 %) of ADRs were local didosis remain an issue. reactions (particularly vaginal ulcerations, vaginal dis- Acquired microbial resistance and spread of intrinsically charge, vulvovaginal pruritus, and vaginal burning sensa- resistant microorganisms as well as bacterial biofilms have tion) which were mostly mild or moderate in intensity. Due to be considered future challenges for an effective treat- to the negligible absorption of DQC, systemic events have ment of vaginal infections. been rarely reported. Furthermore, the available clinical Antibiotics (typically metronidazole and clindamycin) data suggest the suitability of DQC for use during preg- and antimycotics (azoles) are the most recommended nancy also. Vaginal DQC is also listed in the German treatments. In terms of tolerability and safety, vaginal guideline ‘Bacterial vaginosis’ as well as in the Portuguese therapies usually have fewer side effects than oral products. guidelines for treatment of vaginal infections as an effec- Increasing resistances and post-treatment vaginal infections tive treatment for BV [31]. (candidosis after antibacterial therapy, bacterial infections From a clinical point of view DQC could offer an after antimycotic therapy) also have an impact on the attractive treatment for vaginal infections, both for BV and outcome of the therapy. Due to the risk of vaginal infec- VVC as well as in case of mixed infections—this treatment tions causing serious complications in pregnancy, safe concept should be further investigated in broader clinical therapies for pregnant women are also of great importance. studies. Vaginal DQC has been shown to have equal clin- Thus alternative treatments are a key medical need in the ical efficacy as clindamycin in the treatment of BV and to management of vaginal infections. be well tolerated with negligible systemic effects. It has the DQC is an anti-infective agent belonging to the class of major advantage that its broad antimicrobial activity makes quaternary ammonium compounds. Its broad antimicrobial it appropriate for the treatment of mixed vaginal infections activity against all relevant vaginal pathogens is well and in case of uncertain diagnosis. Moreover, resistance of established demonstrated by several investigators over the pathogens is unlikely due to its multiple mode of action, past decades. DQC exhibits a fast and strong bactericidal and vaginal DQC provides also a reduced risk for post- and fungicidal action. The primary mode of action of DQC treatment vaginal infections of different aetiology that is 123 482 Arch Gynecol Obstet (2016) 293:469–484 quite frequent after specific antibacterial or antimycotic vaginal flora that is distinct from bacterial vaginosis: aerobic treatment. vaginitis. Brit J Obstet Gynecol 109:34–43 12. Gardner HL (1968) Desquamative inflammatory vaginitis: a In conclusion, the current formulation DQC 10 mg newly defined entity. Am J Obstet Gynecol 102(8):1102–1105 Ò vaginal tablets (Fluomizin ) as 6-day therapy with its 13. Sobel JD, Reichman O, Misra D, Yoo W (2011) Prognosis and broad antimicrobial spectrum and excellent tolerability treatment of desquamative inflammatory vaginitis. Obstet offers a safe and effective option for empiric therapy of Gynecol 117(4):850–855 14. Sobel JD, Subramanian C, Foxman B, Fairfax M, Gygax SE different vaginal infections in daily practice. (2013) Mixed vaginitis-more than coinfection and with therapeutic implications. Curr Infect Dis Rep 15(2):104–108 Acknowledgments The authors would like to thank Gabriela 15. Donders GG, Zodzika J, Rezeberga D (2014) Treatment of Zwyssig, Medinova AG, Switzerland for comments on the bacterial vaginosis: what we have and what we miss. Expert manuscript. Opin Pharmacother 15(5):645–657 16. Powell AM, Nyirjesy P (2014) Recurrent vulvovaginitis. Best Compliance with ethical standards Pract Res Clin Obstet Gynaecol 28(7):967–976 17. Barbes C, Boris S (1999) Potential role of lactobacilli as pro- Conflict of interest Dr. Ernst Rainer Weissenbacher and Dr. Stefan phylactic agents against genital pathogens. AIDS Patient Care Gerber are members of Global Advisory Board of Medinova AG, STDS 13(12):747–751 Switzerland. Dr. Werner Mendling received honorary from Medinova 18. Hay P (2009) Recurrent bacterial vaginosis. Curr Opin Infect AG. Dr. Philipp Grob and Dr. Valdas Prasauskas are employees of Dis 22(1):82–86 Medinova AG, Switzerland. 19. Reid G, Bruce AW, McGroarty JA, Cheng K-J, Costerton JW (1990) Is there a role for lactobacilli in prevention of urogenital Financial disclosure This publication and free online access was and intestinal infections? Clin Microbiol Rev 3(4):335–344 sponsored by Medinova AG, Switzerland. 20. Schwebke JR (2009) New concepts in the etiology of bacterial vaginosis. Curr Infect Dis Rep 11(2):143–147 Open Access This article is distributed under the terms of the 21. Sobel JD (2007) Vulvovaginal candidosis. 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