Prevalence of mutations associated with resistance to macrolides and fluoroquinolones in Mycoplasma genitalium: a systematic review and meta-analysis.

BACKGROUND: Mycoplasma genitalium is now recognised as an important bacterial sexually transmitted infection. We summarised data from studies of mutations associated with macrolide and fluoroquinolone resistance in M genitalium to establish the prevalence of resistance. We also investigated temporal trends in resistance and aimed to establish the association between resistance and geographical location. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, and MEDLINE for studies that included data for the prevalence of mutations associated with macrolide and fluoroquinolone resistance in M genitalium published in any language up to Jan 7, 2019. We defined prevalence as the proportion of M genitalium samples positive for key mutations associated with azithromycin resistance (23S rRNA gene, position 2058 or 2059) or moxifloxacin resistance (S83R, S83I, D87N, or D87Y in parC), or both, among all M genitalium samples that were successfully characterised. We used random-effects meta-analyses to calculate summary estimates of prevalence. Subgroup and meta-regression analyses by WHO region and time period were done. This study was registered with PROSPERO, number CRD42016050370. RESULTS: Overall, 59 studies from 21 countries met the inclusion criteria for our study: 57 studies of macrolide resistance (8966 samples), 25 of fluoroquinolone resistance (4003 samples), and 22 of dual resistance to macrolides and fluoroquinolones (3280 samples). The summary prevalence of mutations associated with macrolide resistance among M genitalium samples was 35·5% (95% CI 28·8-42·5); prevalence increased from 10·0% (95% CI 2·6-20·1%) before 2010, to 51·4% (40·3-62·4%) in 2016-17 (p<0·0001). Prevalence of mutations associated with macrolide resistance was significantly greater in samples in the WHO Western Pacific and Americas regions than in those from the WHO European region. The overall prevalence of mutations associated with fluoroquinolone resistance in M genitalium samples was 7·7% (95% CI 4·5-11·4%). Prevalence did not change significantly over time, but was significantly higher in the Western Pacific region than in the European region. Overall, the prevalence of both mutations associated with macrolide resistance and those associated with fluoroquinolone resistance among M genitalium samples was 2·8% (1·3-4·7%). The prevalence of dual resistance did not change significantly over time, and did not vary significantly by geographical region. INTERPRETATION: Global surveillance and measures to optimise the efficacy of treatments-including resistance-guided strategies, new antimicrobials, and antimicrobial combination approaches-are urgently needed to ensure cure in a high proportion of M genitalium infections and to prevent further spread of resistant strains. FUNDING: Australian National Health and Medical Research Council.

Macrolide-resistant Mycoplasma genitalium infections in Cuban patients: an underestimated health problem.

BACKGROUND: The increasing prevalence of macrolide resistant Mycoplasma genitalium is a major concern worldwide. In Cuba, several cases of clinical treatment failure with 1 g single dose and extended azithromycin regimen have been detected and the aim of the present investigation was to retrospectively determine the prevalence of macrolide-resistance mediating mutations (MRMM) in M. genitalium-positive samples conserved at the Cuban National Reference Laboratory of Mycoplasma Research between 2009 and 2016. METHODS: A total of 280 positive DNA extracts were analysed by a 5' nuclease assay for detection of M. genitalium MRMM. Ten urogenital specimens from patients with azithromycin treatment failure and MRMM were inoculated in Vero cell to obtain the isolates for subsequent determination of antimicrobial susceptibility. RESULTS: The overall prevalence of MRMM was 32%. No MRMM was detected in samples collected between 2009 and 2013 but since 2014 a dramatic increase to 90% (95% CI, 76-96%) in 2016 was seen. Three new M. genitalium isolates were isolated in Vero cell cultures and confirmed phenotypic resistance to macrolides in a cell-culture assisted susceptibility test. Preliminary observations suggest that combination therapy with levofloxacin and doxycycline may represent an affordable option for treatment of macrolide resistant M. genitalium infections. CONCLUSIONS: This investigation showed the rapid emergence and high prevalence of MRMM in M. genitalium-infected patients in Cuba and confirmed the phenotypic resistance in isolates carrying MRMM. We suggest that Cuban guidelines for sexually transmitted infections are modified to include testing for M. genitalium and detection of MRMM in patients with failure of syndromic treatment, to ensure that in these cases, the treatment will be guided by etiologic diagnosis.

Aminomethyl Spectinomycins as Therapeutics for Drug-Resistant Gonorrhea and Chlamydia Coinfections.

Bacterial sexually transmitted infections are widespread and common, with Neisseria gonorrhoeae (gonorrhea) and Chlamydia trachomatis (chlamydia) being the two most frequent causes. If left untreated, both infections can cause pelvic inflammatory disease, infertility, ectopic pregnancy, and other sequelae. The recommended treatment for gonorrhea is ceftriaxone plus azithromycin (to empirically treat chlamydial coinfections). Antibiotic resistance to all existing therapies has developed in gonorrheal infections. The need for new antibiotics is great, but the pipeline for new drugs is alarmingly small. The aminomethyl spectinomycins, a new class of semisynthetic analogs of the antibiotic spectinomycin, were developed on the basis of a computational analysis of the spectinomycin binding site of the bacterial 30S ribosome and structure-guided synthesis. The compounds display particular potency against common respiratory tract pathogens as well as the sexually transmitted pathogens that cause gonorrhea and chlamydia. Here, we demonstrate the in vitro potencies of several compounds of this class against both bacterial species; the compounds displayed increased potencies against N. gonorrhoeae compared to that of spectinomycin and, significantly, demonstrated activity against C. trachomatis that is not observed with spectinomycin. Efficacies of the compounds were compared to those of spectinomycin and gentamicin in a murine model of infection caused by ceftriaxone/azithromycin-resistant N. gonorrhoeae; the aminomethyl spectinomycins significantly reduced the colonization load and were as potent as the comparator compounds. In summary, data produced by this study support aminomethyl spectinomycins as a promising replacement for spectinomycin and antibiotics such as ceftriaxone for treating drug-resistant gonorrhea, with the added benefit of treating chlamydial coinfections.

Mycoplasma genitalium and Macrolide Resistance-associated Mutations in the Skåne Region of Southern Sweden 2015.

Mycoplasma genitalium is a sexually transmitted infection ordinarily treated with azithromycin. Emerging resistance to macrolide is linked to mutations in the 23S rRNA gene. We analysed the frequency of such mutations of M. genitalium isolates from patients that were symptomatic, and from sexual partners of symptomatic individuals, from October to December of 2015, in the Skåne Region of Sweden. Mutations were analysed by the use of DNA sequencing. Overall, 11.9% (145/1,311) and 17.0% (116/704) of females and males were positive for M. genitalium, respectively. Macrolide resistant mutations were detected in 13% (31/239) of M. genitalium isolates from first-test patient samples. Twenty-one (8.8%) and 10 (4.2%) of the isolates had point mutations of the 23S-gene at position 2072 and 2071, respectively. Two different M. genitalium isolates were detected simultaneously in two cases. In summary, we found a relatively low rate of macrolide-resistant M. genitalium in the region of Southern Sweden.

Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections.

The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.

Exotic and indigenous problem plants species used, by the Bapedi, to treat sexually transmitted infections in Limpopo Province, South Africa.

BACKGROUND: The ethnic usage of exotics and indigenous problem plants is a highly debated topic, as legislative requirements over-shadow their potential medicinal value, particularly to treat sexually transmitted infections (STIs). Limited information exists regarding their medicinal value among the Bapedi. OBJECTIVES: To ascertain the importance of exotics and indigenous problem plants in the treatment of STIs, a major global primary health care challenge. METHODS: A field observation and semi-structured questionnaire focussing on species diversity, types of STIs treated and medicinal preparation as well as application was used to collect data from 34 traditional healers. RESULTS: Seven exotics and three indigenous problem species were identified. These species were used to treat four STIs; with Catharanthus roseus illustrating its dominance in the treatment of gonorrhoea. Some medicinal species used by Bapedi traditional healers have been validated through scientific research or through their extensive use by various cultures in South Africa and other parts of Africa. To the best of our knowledge Alternanthera pungens, Caesalpinia decapetala, Cinnamomum verum, and Citrullus lanatus are reported for the first time in the treatment of the investigated STIs. CONCLUSIONS: Exotic and indigenous problem species constitute an important component of the STIs treatment protocol. Their utilization by Bapedi cautions against the narrow-minded approach of indiscriminate eradication, as these species can play a significant role in the primary health care needs of socio-economic vulnerable people.

[Antibiotic resistance as a public health problem: the case of genital mycoplasmoses]. / L'antibiotico resistenza un problema di sanità pubblica: il caso delle micoplasmosi genitali.

Antibiotic resistance is an emerging public health problem especially due to the continuous use of antibiotics that selects more aggressive and resistant species. In the present study the authors determined the antibiotic sensitivity of 128 Mycoplasma hominis strains obtained from urethral swabs of male patients (mean age 36 years). The Mycoplasma IST 2 strip was used to test antibiotic susceptibility: 88% of analysed strains were found to be resistant to erythromycin and azithromycin, 75% to clarithromycin, 50% to ofloxacin and ciprofloxacin, and 12% to tetracycline. All strains were susceptible to josamycin, doxycycline and pristinamycin. Results were comparable to those of a recent study by Savarino-Mattei which also showed high resistance of M hominis to macrolide antibiotics and to ciprofloxacin and susceptibility to tetracyclines. Doxycycline is currently the antibiotic of first choice for treating M hominis infections.

Characteristics and dissemination of mosaic penicillin-binding protein 2-harboring multidrug-resistant Neisseria gonorrhoeae isolates with reduced cephalosporin susceptibility in northern Taiwan.

Among 254 Neisseria gonorrhoeae isolates from a sexually transmitted infection (STI) clinic in northern Taiwan, 69 isolates were found to contain the mosaic penA (MA) gene and were associated with elevated cefixime and ceftriaxone MICs. Most of these MA gene-harboring isolates were also resistant to penicillin (71.4%) and ciprofloxacin (100%) and were from men who have sex with men (MSM) or from bisexual men (81.2%). Three major sequence types (ST835, ST2180, and ST2253) constituted 55.7% of these isolates. The major sequence types harboring the mosaic penA gene may represent major sexual networks responsible for the emergence/introduction and the spread of the multidrug-resistant clones in Taiwan.

[Approaches to raising efficacy of treatment of patients with chronic prostatitis associated with intracellular infections].

The efficacy of indigal plus containing indol-3-carbinol, epigallocatexin-3-gallat and Serenoa repens extract in combination with sparfloxacin was studied in a trial with participation of 30 patients with chronic infectious prostatitis associated with intracellular agents. Group 1 (n=15) received indigal plus (2 capsules twice a day for 3 months) and sparfloxacin (200 mg twice a day for 1 month). Group 2 including 15 matched controls received sparfloxacin alone according to the same schedule. The examination included questionnaire survey (IPSS, QoL, NIH-CPSI), blood count, urinalysis, PSA test, microscopy, bacteriological study of prostatic secretion, uroflowmetry, transrectal ultrasound investigation of the prostate with residual urine assay, laser doppleroflowmetry. The examinations were performed on the treatment day 30, 60 and 90. After the antibacterial treatment chlamidia, ureaplasma and E.coli were detected in 13.3, 6.7 and 26.7% patients of the control group, in 6.7, 6.7 and 6.7% patients of the study group, respectively. Thus, the addition of a pathogenetic drug indigal plus to sparfloxacin treatment promoted normalization of apoptosis of the infected cells, led to more effective bacterial eradication, enhanced regression of the symptoms. It is recommended to include indigal plus in a basic scheme of treatment of patients with chronic infectious prostatitis.

[Education for self-administered antibiotic therapy: a pragmatic and ethical alternative for the treatment of STDs for the street youth of Kinshasa in the Democratic Republic of the Congo (RDC)]. / L'éducation à l'antibiothérapie à domicile : alternative pragmatique et éthique de la gestion thérapeutique des IST chez les jeunes de la rue à Kinshasa.

All healthcare providers decide in someone else's place, for someone else. In doing so, they take their place in a long long tradition, that of medical paternalism. Patients are treated as children, incapable of making decisions about themselves. How then are we supposed to deal with patients like the street children of the Democratic Republic of the Congo, who are not part of our health-care system, who refuse care and prescriptions? Their refusal of caregivers forces us to seek strategies to dispel the conflicts, adapt outselves to the situation (self-medication, drug sales outside of dispensaries, etc.), but especially to rethink the relation between caregivers and patients. This does not mean abandoning the authoritarian patriarchal model for total relativism; the use of drugs such as antibiotics is and must remain surrounded by all the precautions necessary to avoid the further development of resistance; it does mean training and informing. The task facing us is that of health education and promotion, a long and continuous process, centered on patients and integrated with their care, aimed at making them capable of managing their disease. This procedure is part of a pragmatic approach: beyond the asymmetry involved in any relationship of power, it is essential to establish informed confidence, to look for adhesion and not constraint. Only this pragmatism can incite young people with sexually transmitted diseases (STDs) to use modern medicine and comply with the dosage instructions. Effective treatment of STDs is, according to WHO, one of the most powerful weapons in the battle against AIDS transmission.

[Update on the epidemiology, diagnosis and treatment of sexually-transmitted infections]. / Panorama actual de la epidemiología, diagnóstico y tratamiento de las infecciones de transmisión sexual.

In the last decade, cases of sexually-transmitted infections (STIs) have progressively increased in Europe. The reasons for this increase are unclear, but may involve changes in social behavior, migration and international travel, coupled with the emergence of risk groups that have not been taken into sufficient consideration to date. The routine use of molecular diagnostic techniques for many of these infections has solved many problems of sensitivity and the suitability of samples for microbiological diagnosis: non-invasive samples can be used, which has undoubtedly contributed to the increase in the number of cases. Moreover, molecular methods have also been introduced for antibiotic and antiviral susceptibility testing, as well as for molecular characterization of clinical isolates. All of these factors, together with the approval of the vaccine against the human papillomavirus, have changed the landscape of STIs across Europe.

[Efficacy of low-intensity laser radiation and antibacterial therapy in the treatment of chronic prostatitis in the presence of sexually transmitted infections].

We studied 94 patients with chronic prostatitis (CP) in combination with urogenital chlamydiasis. The patients were divided into three groups. Group 1 consisted of 32 patients with bacterial prostatitis and sexually transmitted infection (STI). They were treated with fromilid in a dose 500 mg twice a day. Group 2 (n = 27) received also low-intensity laser radiation (LILR) on the prostatic gland. Group 3 patients (n = 35) with abacterial prostatitis were given fromilid (500 mg twice a day). We studied prostatic hemodynamics with color doppler mapping. A specific feature of prostatic vascularisation in CP and STI versus healthy subjects is heterogeneous decline of vessels density in ischemic zones with parallel decrease in these vessels diameter. A peripheral prostatic zone in CP patients with STI was characterized by lower vascularisation than central one. This deteriorates the course of the disease. The results of the study show that adjuvant LILR in CP patients with STI raises efficacy of therapy by 11%. Investigation of prostate vascularisation and hemodynamics of its vessels in CP patients with STI using transrectal ultrasonography and dopplerography provide detailed information about prostatic structure allowing for lesion zones. This facilitates choice of an optimal complex treatment with application of LELR in peripheral inflammation of the prostate.

Antimicrobial activity, toxicity and the isolation of a bioactive compound from plants used to treat sexually transmitted diseases.

Extracts of six ethnobotanically selected medicinal plants (Anredera cordifolia, Elaeodendron transvaalense, Elephantorrhiza burkei, Senna petersiana, Terminalia sericea and Rauvolfia caffra) used traditionally to treat sexually transmitted diseases (STD's) were investigated for antibacterial activity using the agar dilution method. Of the six collected, Terminalia sericea, Senna petersiana and Anredera cordifolia were also investigated for cytotoxicity. The phytochemical studies on Senna petersiana resulted in the isolation of luteolin, which also showed antimicrobial activity. Only the Senna petersiana extract and luteolin isolated from it were tested for antiviral activity and showed some activity at the highest non-toxic concentration of 24 and 500 microg/ml, respectively. The results of the antimicrobial screening support the ethnomedicinal uses of these plants to some extent.

A randomized controlled trial of azithromycin versus doxycycline/ciprofloxacin for the syndromic management of sexually transmitted infections in a resource-poor setting.

A randomized controlled trial was carried out to assess the effectiveness of azithromycin versus a standard regimen with doxycycline/ciprofloxacin in the treatment of sexually transmitted infections in a resource-poor environment. Infection with Chlamydia trachomatis was cured in 23/24 (95.8%) of women in the azithromycin arm versus 19/21 (90.5%) in the doxycycline arm (P = 0.6), resulting in three treatment failures. Gonorrhoea was cured in 55/56 (98.2%) women, with one treatment failure in a patient with concomitant C. trachomatis infection. These results indicate that a single oral dose of azithromycin may prove to be a more effective and convenient treatment for sexually transmitted infections in women in a resource-poor environment

The role of fluoroquinolones in sexually transmitted diseases.

The management of sexually transmitted diseases (STDs) has reached a new level in the era of antibiotic resistance and human immunodeficiency virus infection. To date, no single antimicrobial is capable of eradicating the commonly encountered STD pathogens including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum. Among the marketed fluoroquinolones, ciprofloxacin, ofloxacin, lomefloxacin, and enoxacin all provide excellent in vitro activity (MIC90 < 0.06 micrograms/ml) and excellent in vivo efficacy against N. gonorrhoeae, including multiply resistant isolates (penicillinase-producing N. gonorrhoeae and chromosomally mediated resistant N. gonorrhoeae). Ofloxacin is the only fluoroquinolone approved by the Food and Drug Administration for chlamydial infection. All of the quinolones lack reliable in vitro activity against Ureaplasma urealyticum, a cause of nongonococcal urethritis. Although limited data suggest the usefulness of ciprofloxacin and ofloxacin in the treatment of pelvic inflammatory disease, these drugs cannot currently be recommended for single-agent therapy. Haemophilus ducreyi infections, however, can be managed effectively with the fluoroquinolones. Although their role continues to evolve, this class of drugs cannot be used equally to treat all STDs, and notably, no quinolone to date inhibits T. pallidum.