Introductory Chapter: Bacterial Sexually Transmitted Infections – New Perspectives

1. Introduction

Sexually transmitted infections (STIs) are some of the most common infections worldwide. Newer sexually transmitted pathogens have been recognized and functionally described since 1980, with over 30 such infectious products currently known, which may be bacteria, viruses, or parasites. Today, conditions exist in developing countries that lead to an ever-increasing rate of STIs. Factors that influence this growth are: population explosion, especially in age groups that include teenagers and young people, population migration to urban areas, wars, or poverty. In these countries, in addition to human immunodeficiency virus (HIV) infection, three sexually transmitted bacterial infections (gonorrhea, chlamydia, and syphilis) can be considered among the first to affect the health of the population and reproductive life.

The most common sexually transmitted infection worldwide is chlamydia, with approximately 146 million infections each year. But while trends in increasing numbers of Chlamydia spp. infections appear to have stabilized in recent years, gonorrhea rates have increased, especially among men. The 2013 report on STIs in Europe shows that, in the countries of the European Union and the European Economic Area, STIs differ by age group: young adults between 15 and 25 had only 14% of syphilis cases but had nearly 39% of gonorrhea and 67% of chlamydia cases [1].

The Centers for Diseases Control and Prevention’s (CDC) estimates that the prevalence and cost of STIs in the United States indicate that 20% of the population in this region (about one in five people) had an STI in 2018, infections that have cost that year almost 16 billion dollars in direct medical costs from the budget of the American health system [2].

No STI can be viewed and treated as an isolated infection because multiple infections are very common and the presence of an STI denotes high-risk sexual behavior that may be associated with other infections, which may be more serious. STIs can be classified based on both cause and clinical manifestations. Some of the pathogens can also be transmitted non-sexually, but for each of them, sexual transmission is clinically and epidemiologically important.

Many STIs are caused by bacterial infectious agents. In general, most STIs caused by bacteria are treatable, but if they go undiagnosed or are diagnosed too late, they can seriously affect the health of infected people. Thus, early detection and treatment can reduce the spread of bacterial STIs in the population.

Bacterial vaginosis is known to be highly implicated in female infertility and is probably a major cause of unexplained infertility. Screening and treatment of bacterial vaginitis during infertility treatment has greatly decreased its rate [3].

2. The most common bacterial STI pathogens

Chlamydia trachomatis infections are the most reported STI worldwide. However, it is known that there are many infections caused by this bacterium that go undiagnosed and consequently remain untreated. C. trachomatis can persist for a long time in the genital tract in a resistant form, and symptoms of infection may go unnoticed in about 75–80% of women [4]. Since many cases are asymptomatic, the actual detection of the infection would require screening in the population [5]. It is very important to diagnose this bacterium in the early stages of infection and start treatment as quickly as possible to avoid complications that may occur in the long term, thus reducing the risk of reproductive tract sequelae.

Lymphogranuloma venereum (LGV) is a disease caused by C. trachomatis serotypes L1, L2, and L3. It is considered endemic to Asia, Africa, South America, and the southeastern United States. In Europe, LGV infection is found almost exclusively in men who have sex with men (MSM), presenting clinically as a proctocolitis commonly associated with HIV [6].

Neisseria gonorrhoeae is the etiological agent of gonorrhea, one of the most common bacterial STIs, which is characterized by purulent inflammation of the mucous membranes of the genitourinary system, producing over 82 million new infections worldwide every year. Since 2008, the total number of gonorrhea cases has increased by 79%, especially among men. This increase appears to be related to the increase in cases among MSM [1]. Being a bacterium with remarkable genetic variability has led to the emergence and spread of multidrug-resistant strains of N. gonorrhoeae. This antibiotic resistance and the absence of an effective vaccine are major problems worldwide, highlighting the need for routine surveillance, prevention, and control measures [7].

Treponema pallidum is the etiological agent of syphilis, one of the bacterial STIs known for centuries [8]. Syphilis is a disease characterized by a decades-long clinical course that may include four different stages, without adequate treatment leading to either death or spontaneous resolution after the secondary stage. The overall rate of syphilis has increased since 2010, especially among men. In Europe, the incidence of syphilis has been reported to be five times higher in men than in women, and most cases occur in people over 25 years of age [1]. It is a serious disease because treponemes can cross the hemato-encephalic barrier and trigger neurological signs and symptoms, the risk being higher in patients with immunodeficiency or HIV. Syphilis can be transmitted from mother to unborn child, the stage of the mother’s disease during pregnancy has an important role. If the mother’s infection is massive it will lead to spontaneous abortion, but if there are few pathogens in the mother’s blood, the child will develop congenital syphilis [6]. The upward trend in syphilis rates in many EU countries may be partly explained by increased case finding due to more testing among HIV-positive MSM, as recommended in current HIV management guidelines, or by an improved and more efficient reporting of detected cases.

Mycoplasmas are the smallest free-living microorganisms that lack a cell wall. Genital mycoplasmas are represented by species frequently found in the lower genitourinary tract of sexually active people, the most widespread being Mycoplasma hominis, Ureaplasma urealyticum, and Mycoplasma genitalium. Data suggest that infection with U. urealyticum occurs in 10–50% of women and that with M. hominis in less than 20% of them [9]. Since they have a high prevalence among asymptomatic women, their role in sexually transmitted diseases should be well evaluated [10]. These species of microorganisms are considered to induce a wide spectrum of pathological conditions in the lower urinary tract and genital organs, and M. genitalium would be implicated as a causative agent in conditions with significant sequelae. Some studies have reported that these organisms are involved in female infertility or premature birth [11]. In addition, some studies present mycoplasmas as causative agents of male infertility by changing some sperm characteristics [12].

Klebsiella granulomatis (formerly known as Calymmatobacterium granulomatis) is a gram-negative bacterium, the causative agent of donovanosis, a chronic ulcerative genital disease. The disease rarely occurs in Western European countries but is common in parts of Africa and South America. Transmission is mostly sexual, so infection with this bacterium can be considered an STI.

3. Diagnosis of bacterial STIs

The bacteria that cause STIs are very different from each other, so the methods of detecting bacterial STIs are very varied. Even for the same bacteria, there are different test methods. Substantial differences between testing methods and surveillance systems in different countries mean that many infections go undiagnosed and thus go unreported.

For example, the laboratory diagnosis of syphilis is based primarily on a series of serological tests: a positive screening test followed by a confirmatory test. Since antibodies can only be detected about 3 weeks after infection, the very early stage of the disease cannot be diagnosed serologically. Dark-field microscopy is used for epithelial lesions, and nucleic acid amplification tests (NAATs) have recently been introduced that can be used for direct detection of the causative pathogen [6].

Also, for the detection of C. trachomatis, immunoglobulin antibodies (IgG) persist in the body for years and therefore can be used as markers for infection [13], but the presence of antibodies does not indicate an infection present in the body at the time of detection, so these markers cannot be used in diagnosis.

Although bacterial cultures are considered by some to be the gold standard, some of the bacteria that cause STIs are very difficult to grow on culture media, and therefore most clinicians are unable to correctly assess the presence of one or another STI agent, if use these microbiological methods. For example, M. genitalium is difficult to grow on culture media because it has slow growth, strict nutrient requirements, and suitable culture media is not widely available [14]. On the other hand, due to the difficulties of sample collection, transfer, and storage, these methods show low sensitivity and are not suitable for screening, as some bacteria are fragile and difficult to transport.

New laboratory methods using the Polymerase Chain Reaction (PCR) technique allow rapid and targeted detection of STI pathogens, and the multiplex real-time PCR (RT-PCR) technique can be successfully used for the detection of multiple agents from a single sample STI, considering their association in many cases. These genetic tests allow establishing a diagnosis in a maximum of 2–3 days, with a sensitivity of up to 99%. In contrast, cell cultures provide a sensitivity of 85–95% in acute urethral infections with N. gonorrhoeae and less than 50% in chronic forms in women [15]. These multiplex RT-PCR kits are suitable for the routine detection of these STIs. They have proven to be cost-effective and rapid diagnostic tools with high reliability for the simultaneous detection of multiple pathogens present [16].

4. Treatment of bacterial STIs and resistance to antibiotics

Since its introduction against syphilis, in 1943, penicillin has remained the treatment for this disease, at all stages, and until now, no forms of resistance have been reported [6].

With respect to C. trachomatis, infections unresponsive to tetracycline or doxycycline have been reported, but pathogenic strains of this bacterium showing stable resistance to tetracycline have not yet been isolated from humans [17]. However, in the case of chlamydiosis, it is very likely that the infections will reappear even if adequate treatment has been used. This fact is due to reinfection or relapse, if the bacteria deviate to persistent phenotypes, resistant to antibiotics [18].

The three classes of antibiotics used in the treatment of Ureaplasma spp. are quinolones, tetracyclines, and macrolides, tetracycline being the most frequently used drug in the treatment of U. urealyticum infections [19]. In bacteria, tetracycline resistance is encoded by several genetic determinants, of which TetM is the only tetracycline resistance determinant reported so far in mycoplasmas. Using NAATs, both the presence of mycoplasmas and their resistance to this antibiotic can be determined from a single biological product sample [20].

The biggest problems with antibiotic resistance occur with N. gonorrhoeae. Being a bacterium capable of incorporating and changing DNA, as well as transferring modified DNA sequences, N. gonorrhoeae is known as a bacterium that readily develops mutations. This fact is important both for the development of antibiotic resistance and also has an important role in developing the diagnosis using NAATs, considering that the sensitivity of a certain molecular test can be decreased if the target is a genetically modified region. In recent years, N. gonorrhoeae has become less sensitive to several antibiotics, such as sulfonamides, penicillin, tetracyclines, fluoroquinolones, and even cephalosporins, thus defending multiresistant strains to antibiotics and therefore the appropriate treatment is sometimes difficult to apply. In many countries, dual antimicrobial therapy (ceftriaxone plus azithromycin) is the recommended first-line empiric treatment [21]. Due to the phenomenon of resistance, lately, natural products are increasingly being sought as possible alternative treatments for gonorrhea [22].

Resistance of microorganisms to antibiotics is a very dynamic phenomenon, which highlights the need to update prevalence and susceptibility data in different geographical areas. The use of molecular tests for surveillance of antimicrobial resistance in sexually transmitted bacteria would provide a significant advantage in terms of public health and the treatment of these diseases [23].

5. Transmission and prevention

In recent years, the incidence of STIs seems to have decreased in industrialized countries that make sustained efforts to prevent and combat these infections, but it remains a big problem everywhere in the world, especially in developing countries. To prevent the spread of these infections, there are several approaches, such as: reducing the rate of changing partners, encouraging safer sexual practices, such as the use of condoms, detecting and treating them in early stages, or even introducing screening programs in the population groups with increased risk of contracting such infections. However, there are certain constraints that prevent the effective application of prevention methods such as: the lack of sexual education programs for children and young people, the available time of clinicians, and, finally, the financial aspects regarding the costs for the implementation of modern laboratory methods for accurate detection of the causative pathogen or determination of antibiotic resistance. As the prevalence of bacterial STIs is increasing in the MSM community, a recent pilot study demonstrated the effectiveness of reducing the transmission of these bacterial infections using pre-exposure prophylaxis by daily administration of doxycycline to men in this community [24].

Besides this, there are opinions that claim that vaccination against sexually transmitted pathogens would be indicated, especially in the case of N. gonorrhoeae. This approach can be successful if the origins of antibodies in the genital tract and the mechanisms by which they could exercise protective immunity are elucidated [25]. In recent years, progress has been made regarding the understanding of the molecular basis of the pathogenesis of the infection and the mechanisms of host cell damage, including those of escape from immune surveillance with the aim of obtaining effective vaccines against these bacteria.

Therefore, this book attempts a new approach regarding different aspects of bacterial STIs, presenting points of view, challenges, or individual research, to open new perspectives on this field in order to use advanced methods of diagnosis, treatment, control, and prevention of these infections that affect a large part of the population all over the world.