Solithromycin as A Potential Novel Antibiotic Against Neisseria Gonorrhoeae Resistance

2020 ◽  
Author(s):  
Muhammad Habiburrahman ◽  
Vivian  Soetikno ◽  
Wani Riselia Sirait ◽  
Missy Savira
Keyword(s):  
Clinical Trial ◽  
Neisseria Gonorrhoeae ◽  
Wide Distribution ◽  
Phase Iii ◽  
Financial Loss ◽  
Anatomic Site ◽  
Transmitted Infection ◽  
Sexually Transmitted ◽  
Phase Iii Clinical Trials ◽  
New Treatment

Gonorrhea is one of the most often sexually transmitted infection in the world. In 2016, WHO stated the Southeast Asia region as the fourth-highest incidence rate and prevalence of gonorrhea. One of the current problems with gonorrhea is related to its emerging resistance to first-line drugs such as cephalosporins, macrolides, and fluoroquinolones. This resistance has an impact on the difficulty of finding effective antibiotics to eradicate the infection, thus risking financial loss and infertility in sexually active age patients. This literature review will discuss solithromycin, the first fluoroketolide in phase III clinical trial, and show its potential as a new antibiotic against infection with resistant Neisseria gonorrhoeae. Literatures are searched using Pubmed and Google Scholar search engines with keywords: antibiotics, CEM-101, clinical trial, Neisseria gonorrhoeae, new treatment, pharmacology, pharmacokinetics, resistance, safety, and solithromycin. This semisynthetic antibiotic is supported by a different chemical structure from previous macrolides; improving solithromycin becomes more stable and able to bind easier with bacterial ribosomes. Pharmacologically, solithromycin provides an advantage in its high bioavailability, easy oral administration route, wide distribution, metabolism mainly in the liver, but not required dosage adjustments due to hepatic impairment, and a single dosage preparation that can increase patient compliance in healing gonorrhea infections. Also, its lower MIC50 than previous antibiotics makes it well-tolerated, therefore making this antibiotic as a potential recommendation for the management of multi-drug resistant gonorrhea in the future. Solithromycin is not inferior to the standard therapy (ceftriaxone and azithromycin), with 80% vs. 84% gonorrhea eradication rates. Per the anatomic site, the eradication rate is 92% in genital, 94% in the pharynx, and 83% in the rectum. However, special attention needs to be paid to the side effects of the gastrointestinal tract of solithromycin, as observed in phase III clinical trials at a dose of 1000 mg in the form of diarrhea (24%) and nausea (21%).

scholarly journals Trends in antimicrobial susceptibility for azithromycin and ceftriaxone in Neisseria gonorrhoeae isolates in Amsterdam, the Netherlands, between 2012 and 2015

2017 ◽  
Vol 22 (1) ◽  
Author(s):  
Carolien M Wind ◽  
Maarten F Schim van der Loeff ◽  
Alje P van Dam ◽  
Henry JC de Vries ◽  
Jannie J van der Helm
Keyword(s):  
The Netherlands ◽  
Neisseria Gonorrhoeae ◽  
Treatment Strategies ◽  
Sex Partners ◽  
Hiv Status ◽  
Transmitted Infection ◽  
Sexually Transmitted ◽  
New Treatment ◽  
Sex With Men ◽  
Infection Clinic

Resistance of Neisseria gonorrhoeae to azithromycin and ceftriaxone has been increasing in the past years. This is of concern since the combination of these antimicrobials is recommended as the first-line treatment option in most guidelines. To analyse trends in antimicrobial resistance, we retrospectively selected all consultations with a positive N. gonorrhoeae culture at the sexually transmitted infection clinic, Amsterdam, the Netherlands, from January 2012 through September 2015. Minimum inhibitory concentrations (MICs) for azithromycin and ceftriaxone were analysed per year, and determinants associated with decreased susceptibility to azithromycin (MIC > 0.25 mg/L) or ceftriaxone (MIC > 0.032 mg/L) were assessed. Between 2012 and 2015 azithromycin resistance (MIC > 0.5 mg/L) was around 1.2%, the percentage of isolates with intermediate MICs (> 0.25 and ≤ 0.5 mg/L) increased from 3.7% in 2012, to 8.6% in 2015. Determinants associated with decreased azithromycin susceptibility were, for men who have sex with men (MSM), infections diagnosed in the year 2014, two infected sites, and HIV status (HIV; associated with less decreased susceptibility); for heterosexuals this was having ≥ 10 sex partners (in previous six months). Although no ceftriaxone resistance (MIC > 0.125 mg/L) was observed during the study period, the proportion of isolates with decreased ceftriaxone susceptibility increased from 3.6% in 2012, to 8.4% in 2015. Determinants associated with decreased ceftriaxone susceptibility were, for MSM, infections diagnosed in 2014, and pharyngeal infections; and for heterosexuals, infections diagnosed in 2014 or 2015, being of female sex, and having ≥ 10 sex partners. Continued decrease of azithromycin and ceftriaxone susceptibility will threaten future treatment of gonorrhoea. Therefore, new treatment strategies are warranted.

scholarly journals Simultaneous Evaluation of Diagnostic Assays for Pharyngeal and Rectal Neisseria gonorrhoeae and Chlamydia trachomatis Using a Master Protocol

2019 ◽  
Author(s):  
Sarah B Doernberg ◽  
Lauren Komarow ◽  
Thuy Tien T Tran ◽  
Zoe Sund ◽  
Mark W Pandori ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Neisseria Gonorrhoeae ◽  
Reference Method ◽  
Likelihood Ratios ◽  
Anatomic Site ◽  
Transmitted Infection ◽  
Cross Sectional ◽  
Predictive Values ◽  
Sexually Transmitted ◽  
Percent Agreement

Abstract Background Pharyngeal and rectal Neisseria gonorrhoeae and Chlamydia trachomatis play important roles in infection and antibacterial resistance transmission, but no US Food and Drug Administration (FDA)–cleared assays for detection at these sites existed prior to this study. The objective was to estimate performance of assays to detect those infections in pharyngeal and rectal specimens to support regulatory submission. Methods We performed a cross-sectional, single-visit study of adults seeking sexually transmitted infection testing at 9 clinics in 7 states. We collected pharyngeal and rectal swabs from participants. The primary outcome was positive and negative percent agreement for detection of N. gonorrhoeae and C. trachomatis for 3 investigational assays compared to a composite reference. Secondary outcomes included positivity as well as positive and negative predictive values and likelihood ratios. Subgroup analyses included outcomes by symptom status and sex. Results A total of 2598 participants (79% male) underwent testing. We observed N. gonorrhoeae positivity of 8.1% in the pharynx and 7.9% in the rectum and C. trachomatis positivity of 2.0% in the pharynx and 8.7% in the rectum. Positive percent agreement ranged from 84.8% to 96.5% for different anatomic site infection combinations, whereas negative percent agreement was 98.8% to 99.6%. Conclusions This study utilized a Master Protocol to generate diagnostic performance data for multiple assays from different manufacturers in a single study population, which ultimately supported first-in-class FDA clearance for extragenital assays. We observed very good positive percent agreement when compared to a composite reference method for the detection of both pharyngeal and rectal N. gonorrhoeae and C. trachomatis. Clinical Trials Registration NCT02870101.

scholarly journals Ocriplasmin for the Treatment of Symptomatic Vitreomacular Adhesion/Traction

2015 ◽  
Vol 09 (01) ◽  
pp. 70
Author(s):  
Baruch D Kuppermann ◽  
Keyword(s):  
Clinical Trial ◽  
Treatment Option ◽  
Case Reports ◽  
Clinical Trial Data ◽  
Phase Iii ◽  
Vitreomacular Adhesion ◽  
Additional Tool ◽  
Phase Iii Clinical Trials ◽  
New Treatment ◽  
Clinical Trial Program

Ocriplasmin has recently been introduced as a new treatment option for patients with symptomatic vitreomacular adhesion/vitreomacular traction (VMA/VMT). Understanding its potential as well as its limitations is crucial as it becomes an additional tool in the management of these diseases. In this article the overall efficacy and safety of ocriplasmin are reviewed, focusing on the results from the phase III clinical trials as well as recently published case reports and postmarketing data analysis. Efficacy data from ocriplasmin use in a clinical setting support the subanalysis of the phase III clinical trial data. This analysis demonstrated that certain baseline ocular characteristics, namely focal VMA, and absence of epiretinal membrane, are predictive of VMA resolution. Safety findings show that the overall percentage of patients experiencing adverse events during the clinical trial program was low in ocriplasmin-treated patients. Postmarketing surveillance data corroborate findings from the phase III trials, and provide additional insights into the characterization of the safety profile of this new treatment option.

Ocriplasmin for the Treatment of Symptomatic Vitreomacular Adhesion/Traction

2015 ◽  
Vol 8 (1) ◽  
pp. 55 ◽  
Author(s):  
Baruch D Kuppermann ◽  
Keyword(s):  
Clinical Trial ◽  
Treatment Option ◽  
Case Reports ◽  
Clinical Trial Data ◽  
Phase Iii ◽  
Vitreomacular Adhesion ◽  
Additional Tool ◽  
Phase Iii Clinical Trials ◽  
New Treatment ◽  
Clinical Trial Program

Ocriplasmin has recently been introduced as a new treatment option for patients with symptomatic vitreomacular adhesion/vitreomacular traction (VMA/VMT). Understanding its potential as well as its limitations is crucial as it becomes an additional tool in the management of these diseases. In this article the overall efficacy and safety of ocriplasmin are reviewed, focusing on the results from the phase III clinical trials as well as recently published case reports and postmarketing data analysis. Efficacy data from ocriplasmin use in a clinical setting support the subanalysis of the phase III clinical trial data. This analysis demonstrated that certain baseline ocular characteristics, namely focal VMA, and absence of epiretinal membrane, are predictive of VMA resolution. Safety findings show that the overall percentage of patients experiencing adverse events during the clinical trial program was low in ocriplasmin-treated patients. Postmarketing surveillance data corroborate findings from the phase III trials, and provide additional insights into the characterization of the safety profile of this new treatment option.

scholarly journals Global Network Analysis of Neisseria gonorrhoeae Identifies Coordination between Pathways, Processes, and Regulators Expressed during Human Infection

mSystems ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Ryan McClure ◽  
Ashwini Sunkavalli ◽  
Phillip M. Balzano ◽  
Paola Massari ◽  
Christine Cho ◽  
...  
Keyword(s):  
Network Analysis ◽  
Neisseria Gonorrhoeae ◽  
Treatment Strategies ◽  
High Morbidity ◽  
Gene Coexpression Network ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Gene Coexpression ◽  
New Treatment

ABSTRACT Neisseria gonorrhoeae is a Gram-negative diplococcus that is responsible for the sexually transmitted infection gonorrhea, a high-morbidity disease in the United States and worldwide. Over the past several years, N. gonorrhoeae strains resistant to antibiotics used to treat this infection have begun to emerge across the globe. Thus, new treatment strategies are needed to combat this organism. Here, we utilized N. gonorrhoeae transcriptomic data sets, including those obtained from natural infection of the human genital tract, to infer the first global gene coexpression network of this pathogen. Interrogation of this network revealed genes central to the network that are likely critical for gonococcal growth, metabolism, and virulence, including genes encoding hypothetical proteins expressed during mucosal infection. In addition, network analysis revealed overlap in the response of N. gonorrhoeae to incubation with neutrophils and exposure to hydrogen peroxide stress in vitro. Network analysis also identified new targets of the gonococcal global regulatory protein Fur, while examination of the network neighborhood of genes allowed us to assign additional putative categories to several proteins. Collectively, the characterization of the first gene coexpression network for N. gonorrhoeae described here has revealed new regulatory pathways and new categories for proteins and has shown how processes important to gonococcal infection in both men and women are linked. This information fills a critical gap in our understanding of virulence strategies of this obligate human pathogen and will aid in the development of new treatment strategies for gonorrhea. IMPORTANCE Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection (STI) gonorrhea, a disease with high morbidity worldwide with an estimated 87 million cases annually. Current therapeutic and pharmacologic approaches to treat gonorrhea have been compromised by increased antibiotic resistance worldwide, including to the most recent FDA-approved antibiotic. New treatment strategies are urgently needed to combat this organism. In this study, we used network analysis to interrogate and define the coordination of pathways and processes in N. gonorrhoeae. An analysis of the gonococcal network was also used to assign categories to genes and to expand our understanding of regulatory strategies. Network analysis provides important insights into pathogenic mechanisms of this organism that will guide the design of new strategies for disease treatment.

scholarly journals Prevalence of urogenital, anal, and pharyngeal infections with Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium: a cross-sectional study in Reunion island

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
A. Calas ◽  
N. Zemali ◽  
G. Camuset ◽  
J. Jaubert ◽  
R. Manaquin ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Neisseria Gonorrhoeae ◽  
Mycoplasma Genitalium ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Transmitted Infection ◽  
Cross Sectional ◽  
Sexually Transmitted ◽  
Urogenital Infection ◽  
High Prevalence

Abstract Background Recommendations for sexually transmitted infection (STI) screening vary significantly across countries. This study evaluated the prevalence of urogenital and extragenital infections with Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Mycoplasma genitalium (MG) in patients visiting a French STI clinic in the Indian Ocean region to determine whether current STI screening practices should be updated. Methods This cross-sectional study examined all patients who visited the STI clinic between 2014 and 2015. Triplex polymerase chain reaction screening for CT, NG, and MG was performed on urine, vaginal, pharyngeal, and anal specimens (FTD Urethritis Basic Kit, Fast Track Diagnostics, Luxembourg). Results Of the 851 patients enrolled in the study, 367 were women (367/851, 43.2%) and 484 were men (484/851, 56.0%). Overall, 826 urogenital specimens (826/851, 97.1%), 606 pharyngeal specimens (606/851, 71.2%), and 127 anal specimens (127/851, 14.9%) were taken from enrolled patients. The prevalence of urogenital CT and MG was high in women ≤25 years (19/186, 10.21%; 5/186, 2.69%) and in men who have sex with women ≤30 years (16/212, 7.54%; 5/212, 2.36%). Among patients with urogenital CT infection, 13.7% (7/51) had urethritis. All patients with urogenital MG infection were asymptomatic. Men who have sex with men had a high prevalence of pharyngeal CT (2/45, 4.44%) and NG (3/44, 6.81%) and a high prevalence of anal CT (2/27, 7.41%), NG (2/27, 7.40%), and MG (1/27, 3.70%). After excluding patients with concomitant urogenital infection, extragenital infections with at least 1 of the 3 pathogens were found in 20 swabs (20/91, 21.9%) taken from 16 patients (16/81, 19.7%), all of them asymptomatic. Conclusions Routine multisite screening for CT, NG, and MG should be performed to mitigate the transmission of STIs in high-risk sexually active populations.

scholarly journals The case for introducing pre-registered confirmatory pharmacological pre-clinical studies

2018 ◽  
Vol 38 (5) ◽  
pp. 749-754 ◽  
Author(s):  
Olivia Kiwanuka ◽  
Bo-Michael Bellander ◽  
Anders Hånell
Keyword(s):  
Clinical Trial ◽  
Traumatic Brain Injury ◽  
Clinical Trials ◽  
Brain Injury ◽  
Network Analysis ◽  
Clinical Studies ◽  
Phase Iii ◽  
Phase Iii Clinical Trial ◽  
Phase Iii Clinical Trials ◽  
Experimental Drugs

When evaluating the design of pre-clinical studies in the field of traumatic brain injury, we found substantial differences compared to phase III clinical trials, which in part may explain the difficulties in translating promising experimental drugs into approved treatments. By using network analysis, we also found cases where a large proportion of the studies evaluating a pre-clinical treatment was performed by inter-related researchers, which is potentially problematic. Subjecting all pre-clinical trials to the rigor of a phase III clinical trial is, however, likely not practically achievable. Instead, we repeat the call for a distinction to be made between exploratory and confirmatory pre-clinical studies.

scholarly journals A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

2007 ◽  
Vol 89 (3) ◽  
pp. 207-211 ◽  
Author(s):  
JF Thorpe ◽  
S Jain ◽  
TH Marczylo ◽  
AJ Gescher ◽  
WP Steward ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Prevention ◽  
Age Of Onset ◽  
Cancer Chemoprevention ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Prostate Cancer Prevention ◽  
Phase Iii Trials

INTRODUCTION Prostate cancer is an excellent target for chemoprevention strategies; given its late age of onset, any delay in carcinogenesis would lead to a reduction in its incidence. This article reviews all the completed and on-going phase III trials in prostate cancer chemoprevention. PATIENTS AND METHODS All phase III trials of prostate cancer chemoprevention were identified within a Medline search using the keywords ‘clinical trial, prostate cancer, chemoprevention’. RESULTS In 2003, the Prostate Cancer Prevention Trial (PCPT) became the first phase III clinical trial of prostate cancer prevention. This landmark study was terminated early due to the 24.8% reduction of prostate cancer prevalence over a 7-year period in those men taking the 5α-reductase inhibitor, finasteride. This article reviews the PCPT and the interpretation of the excess high-grade prostate cancer (HGPC) cases in the finasteride group. The lack of relationship between cumulative dose and the HGPC cases, and the possible sampling error of biopsies due to gland volume reduction in the finasteride group refutes the suggestion that this is a genuine increase in HGPC cases. The other on-going phase III clinical trials of prostate cancer chemoprevention – the REDUCE study using dutasteride, and the SELECT study using vitamin E and selenium – are also reviewed. CONCLUSIONS At present, finasteride remains the only intervention shown in long-term prospective phase III clinical trials to reduce the incidence of prostate cancer. Until we have the results of trials using alternative agents including the on-going REDUCE and SELECT trials, the advice given to men interested in prostate cancer prevention must include discussion of the results of the PCPT. The increased rate of HGPC in the finasteride group continues to generate debate; however, finasteride may still be suitable for prostate cancer prevention, particularly in men with lower urinary tract symptoms.

scholarly journals Epidemiology, molecular characterisation and antimicrobial susceptibility of Neisseria gonorrhoeae isolates in Madrid, Spain, in 2016

2019 ◽  
Vol 147 ◽  
Author(s):  
M. D. Guerrero-Torres ◽  
M. B. Menéndez ◽  
C. S. Guerras ◽  
E. Tello ◽  
J. Ballesteros ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Antimicrobial Susceptibility ◽  
Strong Association ◽  
Clinical Samples ◽  
Transmitted Infection ◽  
Sexually Transmitted ◽  
High Incidence ◽  
Ciprofloxacin Resistance ◽  
Sequence Types ◽  
Infection Clinic

Abstract With the aim to elucidate gonococcal antimicrobial resistance (AMR)–risk factors, we undertook a retrospective analysis of the molecular epidemiology and AMR of 104 Neisseria gonorrhoeae isolates from clinical samples (urethra, rectum, pharynx and cervix) of 94 individuals attending a sexually transmitted infection clinic in Madrid (Spain) from July to October 2016, and explored potential links with socio-demographic, behavioural and clinical factors of patients. Antimicrobial susceptibility was determined by E-tests, and isolates were characterised by N. gonorrhoeae multi-antigen sequence typing. Penicillin resistance was recorded for 15.4% of isolates, and most were susceptible to tetracycline, cefixime and azithromycin; a high incidence of ciprofloxacin resistance (~40%) was found. Isolates were grouped into 51 different sequence types (STs) and 10 genogroups (G), with G2400, ST5441, ST2318, ST12547 and G2992 being the most prevalent. A significant association (P = 0.015) was evident between HIV-positive MSM individuals and having a ciprofloxacin-resistant strain. Likewise, a strong association (P = 0.047) was found between patient age of MSM and carriage of isolates expressing decreased susceptibility to azithromycin. A decrease in the incidence of AMR gonococcal strains and a change in the strain populations previously reported from other parts of Spain were observed. Of note, the prevalent multi-drug resistant genogroup G1407 was represented by only three strains in our study, while the pan-susceptible clones such as ST5441, and ST2318, associated with extragenital body sites were the most prevalent.

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