Could Intensive Screening for Gonorrhea/Chlamydia in Preexposure Prophylaxis Cohorts Select for Resistance? Historical Lessons From a Mass Treatment Campaign in Greenland.

INTRODUCTION: Neisseria gonorrhoeae has developed resistance to all classes of antimicrobials used against it. Current strategies to prevent the emergence of pan-resistance include increased gonorrhea screening in high-prevalence populations such as men who have sex with men taking HIV preexposure prophylaxis. By increasing antimicrobial exposure, others have argued that intensive screening may inadvertently promote the emergence of antimicrobial resistance. AIM/METHODOLOGY: To contribute to this discussion, we conducted a historical review of the effect of a mass gonorrhea treatment campaign in Greenland from 1965 to 1968 on the incidence of gonorrhea and antimicrobial resistance. We conducted a literature review using PubMed and Google Scholar to find relevant studies. Data on the incidence of gonorrhea, antimicrobial susceptibility, and antimicrobials dispensed were extracted and analyzed. RESULTS: Eight articles were found with relevant information. The cornerstone of the campaign involved the repeated treatment for all persons with a diagnosis of gonorrhea in the past 6 months as well as all remaining unmarried persons between 15 and 30 years of age. There was a small and temporary decline in the incidence of gonorrhea during the campaign. The campaign was, however, associated with an increase in the proportion of gonococci that were not susceptible to penicillin. Gonococcal incidence continued to climb after the campaign ended but did decline dramatically after reductions in risk behavior after the global AIDS epidemic. DISCUSSIONS: The mass gonorrhea treatment campaign in Greenland was associated with only a temporary decline in the incidence of gonorrhea. It was, however, followed by an increase in penicillin nonsusceptibility. Intense gonorrhea screening and treatment strategies should be aware of the risk of inducing antimicrobial resistance.

Medicinal leech antimicrobial peptides lacking toxicity represent a promising alternative strategy to combat antibiotic-resistant pathogens.

The rise of antibiotic resistance has necessitated the development of alternative strategies for the treatment of infectious diseases. Antimicrobial peptides (AMPs), components of the innate immune response in various organisms, are promising next-generation drugs against bacterial infections. The ability of the medicinal leech Hirudo medicinalis to store blood for months with little change has attracted interest regarding the identification of novel AMPs in this organism. In this study, we employed computational algorithms to the medicinal leech genome assembly to identify amino acid sequences encoding potential AMPs. Then, we synthesized twelve candidate AMPs identified by the algorithms, determined their secondary structures, measured minimal inhibitory concentrations against three bacterial species (Escherichia coli, Bacillus subtilis, and Chlamydia thrachomatis), and assayed cytotoxic and haemolytic activities. Eight of twelve candidate AMPs possessed antimicrobial activity, and only two of them, 3967 (FRIMRILRVLKL) and 536-1 (RWRLVCFLCRRKKV), exhibited inhibition of growth of all tested bacterial species at a minimal inhibitory concentration of 10 µmol. Thus, we evidence the utility of the developed computational algorithms for the identification of AMPs with low toxicity and haemolytic activity in the medicinal leech genome assembly.

In vitro efficacy of povidone iodine and hydroxyethyl cellulose, alone and in combination, against common feline ocular pathogens.

Infectious ocular disease, such as conjunctivitis, is common in cats and can be caused by several viruses and bacteria, either as a single infection or as co-infections. In this study, povidone-iodine (PVP-I), alone or compounded with hydroxyethyl cellulose (HEC), was investigated for its efficacy against these pathogens in vitro. Whilst PVP-I alone was effective at inhibiting feline herpesvirus type 1 (FHV-1), Chlamydia felis, and Mycoplasma felis, PVP-I with HEC exerted a synergistic inhibitory effect against FHV-1 and C. felis. In contrast, only minimal inhibition of feline calicivirus was observed. These results demonstrate that PVP-I, alone and in combination with HEC, is effective against some feline ocular pathogens when tested in cell lines in vitro. In vivo studies investigating the systemic safety, ocular tolerance, and clinical efficacy of this combination in cats would be necessary before it could be recommended as a therapy in affected cats.

Chlamydia spp. development is differentially altered by treatment with the LpxC inhibitor LPC-011.

BACKGROUND: Chlamydia species are obligate intracellular bacteria that infect a broad range of mammalian hosts. Members of related genera are pathogens of a variety of vertebrate and invertebrate species. Despite the diversity of Chlamydia, all species contain an outer membrane lipooligosaccharide (LOS) that is comprised of a genus-conserved, and genus-defining, trisaccharide 3-deoxy-D-manno-oct-2-ulosonic acid Kdo region. Recent studies with lipopolysaccharide inhibitors demonstrate that LOS is important for the C. trachomatis developmental cycle during RB- > EB differentiation. Here, we explore the effects of one of these inhibitors, LPC-011, on the developmental cycle of five chlamydial species. RESULTS: Sensitivity to the drug varied in some of the species and was conserved between others. We observed that inhibition of LOS biosynthesis in some chlamydial species induced formation of aberrant reticulate bodies, while in other species, no change was observed to the reticulate body. However, loss of LOS production prevented completion of the chlamydial reproductive cycle in all species tested. In previous studies we found that C. trachomatis and C. caviae infection enhances MHC class I antigen presentation of a model self-peptide. We find that treatment with LPC-011 prevents enhanced host-peptide presentation induced by infection with all chlamydial-species tested. CONCLUSIONS: The data demonstrate that LOS synthesis is necessary for production of infectious progeny and inhibition of LOS synthesis induces aberrancy in certain chlamydial species, which has important implications for the use of LOS synthesis inhibitors as potential antibiotics.

In vitro activity of a partially purified and characterized bark extract of Castanea sativa Mill. (ENC®) against Chlamydia spp.

Castanea sativa Mill (ENC®), containing tannins against 33 Chlamydia strains, was compared to SMAP-29 with inhibitory effect against C. trachomatis and C. pneumoniae. The ENC® activity against Chlamydia spp. was evaluated determining the lowest concentration to achieve more than half reduction of intact chlamydial inclusions versus controls. ENC® reduced all Chlamydia strains tested at 1 µg/mL, while SMAP-29 induced reductions of C. trachomatis and C. pneumoniae infectivity at 10 µg/mL. A great reduction of C. trachomatis, C. pneumoniae, and C. abortus infectivity was achieved with a 10 µg/mL ENC® concentration, whereas their infectivity was almost inhibited at 100 µg/mL ENC® concentration.

Omadacycline: development of a novel aminomethylcycline antibiotic for treating drug-resistant bacterial infections.

Omadacycline is a first-in-class aminomethylcycline antibiotic that circumvents common tetracycline resistance mechanisms. In vitro omadacycline has potent activity against Gram-positive aerobic bacteria including methicillin-resistant Staphylococcus aureus, penicillin-resistant and multidrug-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus spp. It is also active against common Gram-negative aerobes, some anaerobes and atypical bacteria including Legionella spp. and Chlamydia spp. Ongoing Phase III clinical trials with omadacycline are investigating once daily doses of 100 mg intravenously followed by once-daily doses of 300 mg orally for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This paper provides an overview of the microbiology, nonclinical evaluations, clinical pharmacology and initial clinical experience with omadacycline.

The Lignan-containing Extract of Schisandra chinensis Berries Inhibits the Growth of Chlamydia pneumonia.

The purpose of this study was to investigate the effect and selectivity of an extract of Schisandra chinensis berries against Chlamydia pneumoniae and C. trachomatis. Among the ethnopharmacological uses of the extract from Schisandrae fructus are cough and pneumonia. Therefore we focused on respiratory pathogens. The extract completely inhibited the growth of C. pneumoniae strain CV6 at 250 µg/mL concentration. The inhibition of C. pneumoniae and C. trachomatis growth was dose dependent and established with three different strains. The extract inhibited C. pneumoniae production of infectious progeny in a dose dependent manner. Chlamydia selectivity was elucidated with growth inhibition measurements of three other respiratory bacterial species. A pure compound found in Schisandra chinensis berries, schisandrin B at 20.0 µg/mL concentration inhibited the growth of both C. pneumoniae and C. trachomatis. The extract was found to be non-toxic to the human host cells. These findings highlight the potential of the extract from Schisandra chinensis berries as a source for antichlamydial compounds.

Tetracycline-resistant Chlamydia suis in cases of reproductive failure on Belgian, Cypriote and Israeli pig production farms.

Similar cases of severe reproductive failure associated with the presence of Chlamydia suis in two Belgian, one Cypriote and one Israeli pig farrowing to slaughter farms are presented. Vaginal and rectal swabs from 39 sows were examined by culture and DNA microarray. Nineteen of 23 (83 %) C. suis-positive sows were infected with tetracycline-resistant C. suis strains, as determined by MIC tests. Furthermore, boar semen from a German artificial insemination centre, intended for export, was positive for C. suis. Emergence of tetracycline-resistant C. suis strains was confirmed.

[Optimization of complex treatment in ocular toxoplasmosis and concurrent infections].

137 patients (177 eyes) with verified toxoplasmic uveitis, retinitis, chorioretenitis were observed. Among them 65 patients had concurrent infections: tuberculosis, herpes simplex and chlamydia. Routine ophthalmologic, clinical and laboratory examination was performed. The results of intensive treatment in acute and chronic phases are presented, the staged drug pathogenic treatment including methods of specific therapy, based on differential approach to anti-inflammatory agents use, was provided. Early diagnosis and appropriate management including combined treatment of concurrent infections improves treatment efficacy and allows to achieve excellent results.

[Target-directed search of anti-virulence drugs].

Modern medicine now encounters with problem of the absence of effective antibacterial drugs, which are able to render therapeutic effect on chronic form of infectious process. Thus, the actual objective is to develop essentially new generation of drugs, on the basis of which should lie identification of new bacterial targets playing key role in process of chronization of infection as well as selection of new physiologically active substances, which are able to render highly specific inhibitory effect on selected target. Solving of this objective is possible during realization of new approaches for search and design of new drugs and, first of all, during usage of bioinformatics methods, which enable to identify new biotargets, select most effective chemical compounds-inhibitors and optimize their pharmacological and pharmacokinetic properties. The most promising bacterial target is secretion systems of pathogenic microorganisms participating in realization of their virulent characteristics and playing major role in transition of infectious process in chronic phase. We performed synthesis of and screening for 80 compounds, which allowed to select a range of inhibitors rendering specific target-directed effect on type 3 secretion system of Chlamydia. Obtained data allow to further assess of biological and therapeutic activity of these compounds on developed models of infectious process in vivo.

A summary of preclinical topical microbicide vaginal safety and chlamydial efficacy evaluations in a pigtailed macaque model.

BACKGROUND: The development of topical microbicides represents a new and exciting field in the prevention of sexually transmitted diseases, and it is especially important that candidate products undergo rigorous preclinical safety and efficacy testing before advancing to clinical trials. METHODS: We have developed a standardized protocol for preclinical vaginal safety and efficacy assessment of topical microbicide candidates in a nonhuman primate model. Over 7 years of funding under an NIH contract, we evaluated a total of 28 test compounds for vaginal safety (via colposcopy, vaginal pH, and microflora) and 9 compounds for efficacy against cervical chlamydial infection. In this article, we describe our methods in detail and summarize our results, particularly noting the ability of our model to distinguish products with deleterious effects on the cervicovaginal environment. We also outline the specific criteria used to determine which products should move into efficacy trials and which should be recommended for reformulation to the manufacturer. RESULTS: Overall, we noted acceptable safety profiles for 24 of 28 candidate products. Common findings included a transient decrease in vaginal pH, petechiae, and mild erythema. Four products were associated with significant adverse colposcopic findings including blisters, epithelial abrasions, and friability; all 4 products were successfully reformulated and showed acceptable safety profiles at lower concentrations. No products showed complete protection against cervical chlamydial infection. CONCLUSIONS: The macaque preclinical safety and efficacy model is critical to maintaining the pace of topical microbicide development, which could ultimately offer a significant opportunity for intervention in the global HIV/AIDS epidemic.

Role of Tryptophan supplementation in the treatment of Chlamydia.

Chlamydia trachomatis, an intracellular pathogen, is the leading cause of preventable blindness and sexually transmitted infections in the world. Infection of epithelial cells with Chlamydia results in the production of antigen-specific IFN-gamma -secreting CD4+ and CD8+ T cells. IFN-gamma activates indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan in the host cell. This IDO mediated tryptophan starvation is known to activate genes for persistence in the Chlamydia, which renders antibiotics ineffectiveness against it. Tryptophan supplementation causes reactivation of Chlamydia from persistent into metabolically active forms and then the antibiotics easily eradicate these active forms of Chlamydia. Therefore treating the chronic Chlamydia infection with antibiotics and tryptophan together may lead to better clearance of Chlamydia infection, and may be a better therapeutic approach in the future.

Serotonin and melatonin, neurohormones for homeostasis, as novel inhibitors of infections by the intracellular parasite chlamydia.

OBJECTIVES: Chlamydiae are obligate intracellular bacteria, causing a variety of diseases, i.e. pneumonia, sexually transmitted disease, conjunctivitis and zoonosis. Tryptophan depletion by interferon-gamma (IFN-gamma) is the most important host defence system against chlamydial infection. Thus chlamydial tryptophan metabolism is thought to play key roles for IFN-gamma resistance, persistent infection and host/tissue tropisms. We tested tryptophan derivatives for activity against chlamydia-infected cells. METHODS: Rates of chlamydial infection and sizes of the inclusions were evaluated by in vitro infection using three Chlamydiaceae species, Chlamydia trachomatis, Chlamydophila pneumoniae and Chlamydophila felis, which show significant divergence of tryptophan synthesis genes and different susceptibilities to IFN-gamma. RESULTS: Melatonin and serotonin, which are recognized as neural hormones for maintenance of organism homeostasis, reduced chlamydial infection but not other bacterial growth tested here. Unlike IFN-gamma, melatonin limited infection of all three chlamydiae and the effects were not recovered by tryptophan supplementation. Melatonin treatment only of host cells could diminish infection and the infection reduction was neutralized by a pertussis toxin, an inhibitor of G proteins. Ligands of melatonin and serotonin receptors also hampered infection. CONCLUSIONS: Inhibition mechanisms of chlamydial infection by melatonin and serotonin appear to be different from those of IFN-gamma and involve specific G-protein-coupled receptors. Melatonin is deemed to inhibit early progression of the chlamydial development cycle, such as establishment of intracellular infection and/or conversion from elementary body to reticulate body. Utilization of melatonin, serotonin or their derivatives may be advantageous for harmless prevention of chlamydial infection.

In vitro and in vivo antichlamydial activities of HSR-903, a new fluoroquinolone antibiotic.

The in vitro and in vivo antichlamydial activities of HSR-903 were investigated. The MICs of HSR-903 for different species of chlamydia were 0.016 to 0.063 microg/ml, which were superior to those of conventional fluoroquinolones. The therapeutic effect of HSR-903 in experimental mouse Chlamydia psittaci pneumonia was also excellent and almost equal to that of minocycline and superior to that of ofloxacin. These results indicate that HSR-903 may be useful in the treatment of respiratory infections caused by chlamydiae.

Long-term effects of gamma interferon on chlamydia-infected host cells: microbicidal activity follows microbistasis.

When human monocyte-derived macrophages or a human uroepithelial cell line (T24 cells) was incubated in the presence of gamma interferon (IFN-gamma) for 24 to 48 h and then infected with Chlamydia psittaci, host cells became activated to restrict intracellular C. psittaci growth. A reversal of this inhibition was observed when infected cells were supplemented with excess exogenous tryptophan at the time of infection or at 1 to 3 days after infection. When IFN-gamma-treated, infected cells were incubated for more extended periods of time before the addition of exogenous tryptophan, no recovery of viable chlamydiae was observed. Neither replacement of the IFN-gamma-containing medium with complete medium supplemented with excess tryptophan nor the addition of excess concentrations of all 20 amino acids with and without essential vitamins contributed to the reversal of IFN-gamma-mediated inhibition of chlamydial growth beyond the time when reversal occurred after the addition of exogenous tryptophan alone. These data provide evidence which indicates that although IFN-gamma treatment of host cells initially results in a microbistatic inhibition of intracellular chlamydial development, longer incubations result in microbicidal activity that is irreversible by modulation of essential nutrient levels.