UL. Belkova, SN Kozlov
Department of Clinical Pharmacology and Institute of Antimicrobial Chemotherapy SGMA, Smolensk
The primary means of therapy of urogenital trichomoniasis is the drug of 5-nitroimidazole metronidazole. However, up to 9,5% of infections caused by metronidazole-resistant strains of that bait to treatment failure. Lack of 100% but effective schemes eradiketsii Trichomonas vaginalis When microbial resistance to metronidazole is difficult to choose the tactics of the management of patients with this pathology, and promotes the use of unsustainable and unsafe drugs and their combinations. In a review article presents data on the prevalence and mechanisms of resistance of T. vaginalis to metronidazole and reflects recent views on the problem of drug therapy trichomonas infection caused by metronidazole-resistant strains of the parasite.
Clinical significance of urogenital trichomoniasis
Urogenital trichomoniasis (OGC) is caused by protozoa parasite Trichomonas vaginalis, and is currently one of the most common in the world of sexually transmitted infections (STIs). According to WHO, trichomoniasis each year become ill from 170 to 200 million people [1]. According to national statistics, in 2004 in the Russian Federation registered 350,094 new cases of trichomoniasis, which accounted for 43,8% of all identified STI [2].
Trichomonas infection of the urogenital organs scope of both women and men, with up to half of infections are asymptomatic. However, even in the absence of clinical manifestations of infection with T. vaginalis may lead to adverse effects. For example, shows the relationship between OGC and the development of cervical cancer, inflammatory diseases of the pelvic organs and infertility. Trichomonas infection significantly increases susceptibility to infection with other STIs, including HIV infection [3].
It is essential that trichomoniasis relatively rarely occurs as monoinfection. The majority of patients (70-90%) T. vaginalis is a member of associates of microorganisms, most often involving mycoplasma (47,3%), gonococci (29,1%), gardnerellas (31,4%), ureaplasmas (20,9 %), chlamydia (18.2%) and fungi (15.7%) [4]. One of the factors contributing to the formation of such associates, is the ability of trichomonads to incomplete phagocytosis of various microorganisms and viruses, creating a reservoir of pathogenic flora in the body and protecting it from exposure to factors of the immune system and drugs (drugs) [5]. By virtue of the above cure of trichomonas infection is of particular importance because its presence can cause inefficiency of therapy and relapse of other STIs.
Pharmacotherapy of trichomoniasis and possible reasons for its ineffectiveness
The main means of treatment of trichomonas infection since the introduction into clinical practice in 1960 of metronidazole are the drugs of 5-nitroimidazole (5-NO), and metronidazole is still the most commonly used drug among them [6]. Preparation of 5-NI not only part of the domestic and international recommendations for the treatment of trichomoniasis (see table), but are the only class of drugs whose effectiveness in this pathology is not questioned. Thus, the effectiveness of systemic therapy trichomonas infection metronidazole reaches, while treatment of sexual partners 95% [10), tinidazole - 90-100% [11]. Single dose of drugs at a dose of 2 g is considered preferable because of their market is accompanied by a decrease in dose, an increase of compliance and reduced risk of adverse drug reactions (NLR) [3].
The low efficiency and / or high toxicity of drugs of other groups, including applied before 5-NO, do not allow us to recommend them now for use with trichomonas infection, which limits the range of etiotropic therapy of trichomoniasis one pharmacological group, while keeping their ineffectiveness of significant difficulties in choosing the tactics of management of patients.
Ineffective treatment of ATM may be due to several factors associated with features of both the patient and the parasite. Among the most frequent causes of treatment failure, most authors include enough high compliance of patients and reinfection, although in some articles played a leading role T. vaginalis resistance to metronidazole. Among other possible reasons for this outcome of therapy indicate a lack of absorption of the drug in the gastrointestinal tract, the low level of its delivery to the urogenital organs, inactivation of the vaginal microflora, as well as a low concentration of zinc in blood plasma [3, 12].
According to available data, recurrence of trichomoniasis after therapy with 5-NO group is 20-40% [5], and the main cause of relapse is re-infection, the frequency of which can reach 36% [12]. In addition, even after successful eradication of trichomonads inflammatory process may continue, supporting the concomitant microflora and creating a false impression of medical treatment failure.
Since two of the main reasons for ineffective therapy OGC - low compliance and reinfection, relatively easy to correct, the greatest difficulties is keeping the patients in whom the infection is caused by metronidazole-resistant strains of T. vaginalis.
Epidemiology and mechanisms of resistance of T. vaginalis to metronidazole
The first cases of resistance of T. vaginalis to metronidazole were reported in 1962 [13]. Filed by the Centers for Disease Control (CDC, USA) in 1989 to 5% of all clinical isolates of T. vaginalis in varying degrees, resistant to this drug. It should be noted that the level of resistance of most strains was relatively low and only a few isolates were: high [3]. This trend continued in subsequent years. Thus, testing of 126 clinical strains of T. vaginalis, isolated in 2004-2005. Revealed resistance to metronidazole in 9.5% of isolates, and its level was low at 7.9% of strains, medium or high - at 1.6% [14].
Stability of trichomonads to metronidazole is closely linked to universal for the entire class of 5-NO mechanism of action of the drug. These drugs by themselves do not possess cytotoxicity. Their effect is based on the ability of elementary intracellular restore nitro preparations with the formation of metabolites that damage DNA, thereby producing a bactericidal effect. Activation of 5-NO occurs in gidrogenosomah T. vaginalis (organelles in place of mitochondria and involved in the synthesis of ATP) with pyruvate-ferredoxin oxidoreductase, hydrogenase and other enzymes [3].
The basis of formation of sustainability of trichomonads to 5-NO is the disturbance of the transformation of drugs into active metabolites. Depending on the type of metabolism involved in the process, the resistance is divided into aerobic and anaerobic. The exact mechanisms for the implementation of stability has not been fully elucidated, but according to available data, the aerobic resistance in trichomonads inhibited transcription of the gene coding for the synthesis of ferredoxin, and an anaerobic observed lack of or decrease in activity of pyruvate-ferredoxin oxidoreductase and hydrogenase [3,15].
Aerobic resistance is a major clinically significant mechanism of resistance T. vaginalis to metronidazole. The level of resistance of "wild" strains varies depending on the degree of violation of the above metabolic processes. The possibility of development of aerobic resistance in vivo in patients receiving standard doses of metronidazole for short periods of time. This type of in vitro resistance can be obtained by cultivation of Trichomonas in media containing sublethal concentrations of the drug [3].
Anaerobic resistance is detected mainly in laboratory strains, although there are anecdotal reports on the allocation of these isolates: high in clinical practice [16]. This type of resistance develops in vitro when cultured strains of T. vaginalis in the presence of sublethal doses of metronidazole, with their gradual increase (from 1 to 100 mg / ml) for 12-21 months [3].
Common approaches to therapy of infection caused by resistant strains of T. vaginalis
Recommended tactics of patients with ATM in the ineffectiveness of standard therapy is presented in the table. Inefficient re-use of standard schemes with good patient complains of a lack of opportunities reinfection with a high degree of probability indicates resistance causing infection strain T. vaginalis to the used drug (or drugs). Obtaining objective data on the sensitivity of the causative agent to 5-NO is used to confirm the presence of resistance, to determine its level and to identify drugs active against the strains T. vaginalis.
In general, therapy trichomonas infection caused by metronidazole-resistant strains is reduced to the following options:
-Change in the regime of therapy with metronidazole (dose increase, the increase in the duration of therapy, changes in route of administration, etc.);
-The use of other drugs of 5-NO;
-The use of drugs other groups.
It should be noted that the proven effectiveness with trichomonas infection is restricted to preparations of 5-NO, whereas the data on the positive effects of drugs of other groups are fragmented, contradictory and do not consider them as an adequate therapeutic alternative to 5-NO. In addition, many of them are highly toxic, which limits their application.
Changing the mode of therapy with metronidazole
According to WHO recommendations, cases of trichomoniasis, in which standard regimens are ineffective, can be cured by high (often doubled) doses of metronidazole with increasing duration of therapy [9]. The effectiveness of this approach due to low level in most situations, the stability of T. vaginalis to metronidazole and not exceed 80% [3, 17]. The above tactics are not applicable to the eradication of trichomonads with high levels of resistance, as required to overcome it dose toxic.
In attempts to reduce the dose of metronidazole to its combination with drugs effective in the treatment of trichomoniasis has not been proved or confirmed only anecdotal clinical observations [18], but whether such tactics remains open. According to some authors, intravenous metronidazole in combination with its oral and intravaginal appointment can often reduce the dose of coursework and, accordingly, the risk of NAL, but this tactic is also disputable [11, 17].
The use of other drugs of 5-NO
In the treatment of trichomonas infection caused by metronidazole-resistant strains of T. vaginalis, widely used by other 5-NO. All products of this group have a similar mechanism of action, differ in pharmacokinetic parameters and safety profile. Although a common mechanism of action makes the possibility of cross-resistance of trichomonads to 5-NO, it nevertheless is incomplete and identifies relatively rare [13]. Thus, the input conducted in 2004-2005. study, only 1 (0.8%) of the tested strains of T. vaginalis had a low level of resistance to tinidazole (BMD 50 mg / ml), whereas for metronidazole were resistant to varying degrees, 9.5% of isolates [14].
According to both domestic and international recommendations, tinidazole is the second after metronidazole drug of choice for the treatment of trichomonas infection (see table). Show the equivalence, and in some cases higher clinical and microbiological efficacy of tinidazole compared with metronidazole for single drug therapy at a dose of 2 g [10].
Tinidazole has a longer half-life than metronidazole, and creates in the tissues of higher concentrations. The level of drug in the discharge of mucous membrane of the vagina close to that in blood plasma, indicating a more effective delivery of tinidazole in this area compared with metronidazole [19]. IPC tinidazole on T. vaginalis, incl. metronidazole-resistant strains, lower than that for metronidazole, which is manifested clinical effectiveness of lower doses of tinidazole and development of the NLR more rare when it is used [17]. The effectiveness of single dose of tinidazole by mouth at a dose of 2 g of 90-100% at nerefrakternom ATM [11]. When using high doses (2-3 grams inside and 1-1,5 g intravaginally for 14 days) in the treatment of refractory trichomoniasis this figure rises to 92% [20]. Thus, tinidazole can be considered one of the drugs of choice for the treatment of infections caused by metronidazole-resistant strains of T. vaginalis, but it is necessary to consider the possibility of cross-resistance to it.
Among the other 5-NO, which could potentially be used in the treatment of trichomonas infection include ornidazole, nimorazol, seknidazol, ternidazol and others note that ornidazole and nimorazol TSNIKVI approved for the treatment of trichomonas infection, including its complications and recurrent forms of [8]. Ornidazole and tinidazole like seknidazol have a longer half-life compared with metronidazole. Nimorazol, by contrast, is eliminated quickly. Nevertheless, the drug has a pronounced Antiprotozoals activity, because two of its main metabolite more active than metronidazole metabolites.
Comparative studies on the use of metronidazole and other 5-NI with trichomonas infection showed that acute administration of most drugs in doses of 1,5-2 g accompanied by a good clinical effect with a relatively favorable safety profile [17]. The main factor limiting the use of drugs of 5-NO in the treatment of infections caused by metronidazole-resistant strains of T. vaginalis, is the possibility of a causative agent cross-resistance.
The use of drugs other groups
The relevance of the use of drugs other than 5-NO, in the treatment of trichomonas infection is caused by the possibility of development in cross-resistance to Trichomonas nitroimidazole. Some of the following drugs were used in the treatment of trichomoniasis before introduction into clinical practice 5-NO, clinical efficacy of several drugs was not investigated or not proven, the possibility of other limited to their high toxicity. Thus, despite the recommendations contained in separate publications, the lack of evidence of efficacy and safety of drugs that do not belong to a group of 5-NO, in the treatment of trichomonas infection, including its refractory forms, does not allow to recommend their use in patients with this pathology, except in cases where other therapeutic alternatives have been exhausted.
Certain effective in the treatment of trichomonas infection have fluconazole, butokonazol, gamitsin, atsetarsol, Paromomycin, furazolidone, mebendazole, and vaccine SolkoTrihovak.
Fluconazole, butokonazol. Some azoles, including fluconazole and butokonazol have in vitro activity against T. vaginalis [21], but data on their effective use in clinical practice is limited mostly combination therapy with 5-NO [18].
Gamitsin. This fully aromatic, similar in structure to amphotericin B, has the ability to induce the death of T. vaginalis by the formation of pores in the cytoplasmic membrane, causing leakage of cytoplasm and cell death. In in vitro studies shows bactericidal effect of low concentrations of the drug against both sensitive and resistant strains to metronidazole T. vaginalis. Gamitsin in the form of local forms used at present in India for the treatment of trichomonas infection, but marked toxicity limits its widespread use [22].
Atsetarsol. This Antiprotozoals drug is an organic derivative of arsenic acid, previously used in the treatment of trichomonas infection, but at present its use is not recommended due to high toxicity and low clinical efficacy [23].
Paromomycin (monomitsin). The effectiveness of topical Paromomycin, an antibiotic class of aminoglycosides, is shown in 7 of 12 patients infected with metronidazole-resistant strains of T. vaginalis, but heavy NAL, such as soreness and ulceration of the mucous membranes, limit the clinical use of the drug [20].
Furazolidone, mebendazole. Antiprotozoals drug furazolidone and worming remedy mebendazole in in vitro studies show high activity against metronidazole-resistant strains of T. vaginalis, indicating the possibility of their local (at the very low systemic bioavailability) use in the treatment of trichomonas infection [24, 25]. At the same time, describes cases of clinical failure of mebendazole with trichomonas infection caused by metronidazole-resistant strains [26]. In addition, both drugs have a relatively high toxicity [17].
SolkoTrihovak. According to some authors, there is a growing resistance of trichomonads to 5-NO vaccination could be an important component of a comprehensive treatment of refractory trichomoniasis. To date, only one developed a vaccine, active against T. vaginalis, - SolkoTrihovak, which was introduced into clinical practice in the late 1970's. It is an inactivated lyophilisates morphologically altered (aberrant) Lactobacillus acidophilus, isolated from the vagina of women suffering from ATM. The mechanism of action of vaccine is the induction of antibody against aberrant lactobacilli. Since microorganisms are able to exchange surface antigens within the ecological community, antibodies to aberrant lactobacilli exhibit some activity in respect of Trichomonas. The effect of the vaccine is linked, presumably, not with a direct effect on T. vaginalis, but with an increase in nonspecific immune protection, which reduces the severity of clinical symptoms and helps eliminate trichomonads [5, 17,27].
Although initially the vaccine was recommended as a means of prevention and treatment of trichomonas infections, further studies questioned the effectiveness of its use as monotherapy in this pathology. At the same time found that the application SolkoTrihovaka in combination with 5-NI in refractory trichomoniasis was accompanied by a decrease in clinical manifestations of infection and reduces the dose of drugs [5, 17].
Conclusion
Defining tactics of patients with trichomonas infection caused by metronidazole-resistant strains of the pathogen still causes trouble, because 5-NO are the only means of therapy of trichomoniasis with proven effectiveness. The low efficiency and / or high toxicity of drugs of other groups, including applied before 5-NO, do not allow us to recommend them now for use with trichomonas infection, except in cases where other therapeutic alternatives have been exhausted. This situation necessitates the development of new effective antitrihomonadnyh drugs that do not belong to a group of 5-NO.
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