cem-101 and Gonorrhea

Neisseria gonorrhoeae, the causative agent of gonorrhoea, has rapidly evolved from an exquisitely susceptible pathogen into a 'superbug' with the capacity to exhibit an extensively drug resistant (XDR) phenotype. The threat of untreatable gonorrhoea now looms on the horizon while the arsenal of effective antimicrobial agents diminishes with time. Ceftriaxone remains the mainstay of first-line therapy as a single agent or as the backbone of a dual therapy regimen. The implementation of new assays to facilitate 'precision' treatment, based on the prediction of N. gonorrhoeae susceptibility to old anti-gonococcal drugs, may enable sparing use of ceftriaxone in those countries that can afford this technology. A few existing drugs, such as ertapenem, can be repositioned to help manage multi-drug resistant and XDR gonorrhoea. Recent clinical trials involving solithromycin and delafloxacin have generated disappointing results in that both agents failed to show non-inferiority to conventional ceftriaxone-based regimens. At present, zoliflodacin and gepotidacin appear to be the most promising antimicrobial agents in clinical development. Both drugs performed well in eradicating urogenital gonorrhoea in recent Phase 2 trials; however, treatment failures were reported at the oropharyngeal site, which is an important site of infection in men who have sex with men and sex workers. Given this observation, it is unlikely that either of these new agents could be promoted for monotherapy of gonorrhoea. The pre-clinical pipeline remains relatively empty of agents likely to progress to clinical development for gonorrhoea treatment and increased investment into gonorrhoea-specific drug discovery is recommended.

Topics: Acenaphthenes; Anti-Bacterial Agents; Barbiturates; Drug Development; Drug Resistance, Multiple, Bacterial; Gonorrhea; Heterocyclic Compounds, 3-Ring; Humans; Isoxazoles; Macrolides; Morpholines; Neisseria gonorrhoeae; Oxazolidinones; Spiro Compounds; Triazoles

Solithromycin is a macrolide antibiotic that has undergone review for the treatment of community-acquired bacterial pneumonia. Solithromycin is also being investigated and has shown promise for the treatment of gonorrhea. With increasing antibiotic resistance, the development of novel antibiotics to combat infections is essential. The unique ribosome-binding stability of solithromycin and mild side effect profile make this a promising new antibiotic. This article will provide an overview on the mechanism of action, clinical efficacy, and safety of this drug for the treatment of gonorrhea. Relevant data were identified through a comprehensive literature search using multiple databases using the keywords solithromycin, CEM-101, and gonorrhea.

Topics: Anti-Bacterial Agents; Clinical Trials as Topic; Drug Resistance, Bacterial; Gonorrhea; Humans; Macrolides; Treatment Outcome; Triazoles

The emergence of high-level resistance to ceftriaxone is giving rise to serious concern about absence of effective treatment options to cure gonococcal infections. Increasing the dosage regimen can be applied to ceftriaxone and azithromycin, but the emergence of high-level resistance has already been reported. Spectinomycin is another active drug but has low efficacy in the treatment of pharyngeal gonorrhoea. Conventional antibiotics could be introduced for gonococcal treatment, but they have some limitations, such as the absence of clinical trials and breakpoint. Combining antibiotics is another promising method to cure patients and to prevent the emergence of resistance. The most important strategy to maintain the efficacy of antibiotics is rapid detection and dissemination control of novel resistant isolate.

Topics: Anti-Bacterial Agents; Azithromycin; Barbiturates; Ceftriaxone; Drug Resistance, Bacterial; Drug Therapy, Combination; Gonorrhea; Humans; Isoxazoles; Macrolides; Morpholines; Neisseria gonorrhoeae; Neisseriaceae Infections; Oxazolidinones; Pharyngitis; Spectinomycin; Spiro Compounds; Triazoles

The goal of the Sexually Transmitted Infection Clinical Trial Group's Antimicrobial Resistance (AMR) in Neisseria gonorrhoeae (NG) meeting was to assemble experts from academia, government, nonprofit and industry to discuss the current state of research, gaps and challenges in research and technology and priorities and new directions to address the continued emergence of multidrug-resistant NG infections. Topics discussed at the meeting, which will be the focus of this article, include AMR NG global surveillance initiatives, the use of whole genome sequencing and bioinformatics to understand mutations associated with AMR, mechanisms of AMR, and novel antibiotics, vaccines and other methods to treat AMR NG. Key points highlighted during the meeting include: (i) US and International surveillance programs to understand AMR in NG; (ii) the US National Strategy for combating antimicrobial-resistant bacteria; (iii) surveillance needs, challenges, and novel technologies; (iv) plasmid-mediated and chromosomally mediated mechanisms of AMR in NG; (v) novel therapeutic (eg, sialic acid analogs, factor H [FH]/Fc fusion molecule, monoclonal antibodies, topoisomerase inhibitors, fluoroketolides, LpxC inhibitors) and preventative (eg, peptide mimic) strategies to combat infection. The way forward will require renewed political will, new funding initiatives, and collaborations across academic and commercial research and public health programs.

Topics: Anti-Bacterial Agents; Antimicrobial Stewardship; Bacterial Vaccines; Barbiturates; Drug Resistance, Multiple, Bacterial; Epidemiological Monitoring; Gonorrhea; Group Processes; Humans; Isoxazoles; Macrolides; Microbial Sensitivity Tests; Morpholines; Mutation; Neisseria gonorrhoeae; Oxazolidinones; Public Health; Sexually Transmitted Diseases; Spiro Compounds; Topoisomerase Inhibitors; Triazoles; World Health Organization

Antibiotic-resistant gonorrhoea represents a global public health threat, and new therapies are needed. We aimed to compare the efficacy and safety of solithromycin, a fourth generation macrolide, with ceftriaxone plus azithromycin for the treatment of gonorrhoea.. We did an open-label, multicentre, non-inferiority trial of patients aged 15 years or older with uncomplicated untreated genital gonorrhoea at two sites in Australia and one site in the USA. Patients were randomly assigned (1:1) to receive single dose oral solithromycin 1000 mg or intramuscular ceftriaxone 500 mg plus oral azithromycin 1000 mg. Neisseria gonorrhoeae cultures were obtained at baseline and test of cure (day 7 ± 2). The primary outcome was the proportion of patients with eradication of genital N gonorrhoeae based on culture at test of cure, assessed in the microbiological intention-to-treat (mITT) population, which included all randomly assigned patients who received any dose of study drug and had a positive genital culture for N gonorrhoeae at baseline. Non-inferiority of solithromycin was to be concluded if the lower limit of the 95% CI for the between-group differences was greater than -10%. Safety was analysed in all patients who received any dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02210325.. Between Sept 3, 2014, and Aug 27, 2015, 262 patients were randomly assigned and 261 received treatment (130 in the solithromycin group and 131 in the ceftriaxone plus azithromycin group). In the mITT population, 99 (80%) of 123 patients in the solithromycin group and 109 (84%) of 129 patients in the ceftriaxone plus azithromycin group had N gonorrhoeae eradication at test of cure (difference -4·0%, 95% CI -13·6 to 5·5), thus solithromycin did not meet the criterion for non-inferiority at the prespecified -10% margin. The frequency of adverse events was higher in the solithromycin group than the ceftriaxone plus azithromycin group (69 [53%] of 130 patients vs 45 [34%] of 131 patients), the most common of which were diarrhoea (31 [24%] of 130 patients vs 20 [15%] of 131 patients), and nausea (27 [21%] of 130 patients vs 15 [11%] of 131 patients).. Solithromycin as a single 1000 mg dose is not a suitable alternative to ceftriaxone plus azithromycin as first-line treatment for gonorrhoea. If insufficient duration of solithromycin exposure at the infection site in a subset of individuals was the reason for treatment failures, this might be adequately addressed with dose adjustment. However, any further trials with longer dosing need to consider the potential risk of gastrointestinal effects and liver enzyme elevations.. Cempra Pharmaceuticals.

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Australia; Azithromycin; Ceftriaxone; Female; Gonorrhea; Humans; Injections, Intramuscular; Macrolides; Male; Neisseria gonorrhoeae; Treatment Outcome; Triazoles; United States

Progressive resistance to antimicrobial agents has reduced options for gonorrhea therapy worldwide. Solithromycin (CEM-101) is a novel oral fluoroketolide antimicrobial with substantial in vitro activity against Neisseria gonorrhoeae.. We conducted a phase 2 trial of 2 oral doses of solithromycin (1200 and 1000 mg) for treatment of uncomplicated gonorrhea.. A total of 59 participants were enrolled and treated in this trial; 28 participants received 1200 mg of solithromycin and 31 received 1000 mg. Forty-six (78%) participants had positive cultures for N. gonorrhoeae at the time of enrollment: 24 of the 28 persons (86%) who received 1200 mg of oral solithromycin, and 22 of 31 (71%) who received 1000 mg. In addition, 8 participants had positive pharyngeal gonococcal cultures, and 4 had positive rectal cultures. All patients with positive cultures for N. gonorrhoeae were cured at all sites of infection. Chlamydia trachomatis and Mycoplasma genitalium coinfections were evaluated using nucleic acid amplification tests and were negative at 1 week of follow-up in 9 of 11 (82%) participants positive for C. trachomatis and 7 of 10 (70%) participants positive for M. genitalium. Mild dose-related gastrointestinal side effects (nausea, loose stools, vomiting) were common but did not limit therapy.. Oral single-dose solithromycin, in doses of 1000 mg and 1200 mg, was 100% effective for treatment of culture-proven gonorrhea at genital, oral, and rectal sites of infection and is a promising new agent for gonorrhea treatment.. NCT01591447.

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Drug Resistance, Bacterial; Female; Gonorrhea; Humans; Macrolides; Male; Middle Aged; Neisseria gonorrhoeae; Triazoles; Young Adult

Topics: Azithromycin; Ceftriaxone; Genitalia; Gonorrhea; Humans; Macrolides; Triazoles

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Gonorrhea; Humans; Macrolides; Neisseria gonorrhoeae; Triazoles

Topics: Azithromycin; Ceftriaxone; Genitalia; Gonorrhea; Humans; Macrolides; Triazoles

Mycoplasma genitalium has become well established as an etiological agent of sexually transmitted infections, but due to its fastidious growth requirements, only a few M. genitalium strains are available to determine the MICs of currently used and new antimicrobial agents. Recent clinical trials have suggested that treatment with azithromycin has decreasing efficacy due to an increasing prevalence of macrolide resistance, and alternative treatment with moxifloxacin is similarly under pressure from emerging resistance. Thus, there is an urgent need for new antimicrobials. The in vitro activity of the newly developed fluoroketolide solithromycin (CEM-101) was evaluated against a collection of 40 M. genitalium strains, including 15 with high-level macrolide resistance and 5 multidrug-resistant strains with resistance to both macrolides and quinolones. Furthermore, the MIC of solithromycin was correlated with mutations in the 23S rRNA gene and in the genes encoding ribosomal proteins L4 and L22. The in vitro results showed that solithromycin has activity against M. genitalium superior to that of other macrolides, doxycycline, and fluoroquinolones. Accordingly, this new fluoroketolide might be an effective option for treatment of M. genitalium infections. However, the efficacy of solithromycin in clinical trials with follow-up for test of cure and detection of genotypic and phenotypic resistance needs to be evaluated prior to widespread use. In a phase 2 clinical trial, solithromycin was highly effective as a single oral dose against C. trachomatis and Neisseria gonorrhoeae, suggesting that solithromycin could be a treatment option for several sexually transmitted infections, including in syndromic treatment of urethral and vaginal discharge.

Topics: Anti-Bacterial Agents; Azithromycin; DNA, Bacterial; DNA, Ribosomal; Doxycycline; Drug Resistance, Bacterial; Fluoroquinolones; Gonorrhea; Humans; Macrolides; Microbial Sensitivity Tests; Moxifloxacin; Mutation; Mycoplasma genitalium; Mycoplasma Infections; Neisseria gonorrhoeae; Triazoles