In vitro activity of WQ-3810, a novel fluoroquinolone, against multidrug-resistant and fluoroquinolone-resistant pathogens

Kazamori, Daichi; Aoi, Hiroshi; Sugimoto, Kaori; Ueshima, Taichi; Amano, Hiroko; Itoh, Kenji; Kuramoto, Yoji; Yazaki, Akira

doi:10.1016/j.ijantimicag.2014.07.017

Cited by 24 publications

(13 citation statements)

References 23 publications

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“…These include several new fluoroquinolones (142–145), tetracyclines (146, 147), carbapenems (148), macrolides (149, 150), and the lipoglycopeptide dalbavancin (151). These and some additional antimicrobials or therapeutic compounds have been recently reviewed elsewhere (11, 12, 22).…”

Section: Future Treatments For Gonorrheamentioning

confidence: 99%

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae : A Major Global Public Health Problem in the 21st Century

2016

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Neisseria gonorrhoeae is a strictly human pathogen that is typically transmitted by sexual contact. The associated disease gonorrhea has plagued humankind for thousands of years, with a current estimated incidence of 78 million cases per year. Advances in antimicrobial discovery in the 1920s and 1930s leading to the discovery of sulfonamides and penicillin begun the era of effective antimicrobial treatment of gonorrhea. Unfortunately, the gonococcus developed decreased susceptibility or even resistance to these initially employed antibiotics, a trend that continued over subsequent decades with each new antibiotic that was brought into clinical practice. As this pattern of resistance has continued into the 21st century, there is now reason for great concern, especially in an era when few new antibiotics have prospects for use as treatment of gonorrhea. Here, we review the history of gonorrhea treatment regimens and gonococcal resistance to antibiotics, the mechanisms of resistance, resistance monitoring schemes that exist in different international settings, global responses to the challenge of resistance, and prospects for future treatment regimens in the 21st century.

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Section: Future Treatments For Gonorrheamentioning

confidence: 99%

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae : A Major Global Public Health Problem in the 21st Century

2016

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“…For example, several new fluoroquinolones, e.g. avarofloxacin (JNJ-Q2), sitafloxacin, WQ-3810, and delafloxacin, have shown relatively high potency against gonococci, including ciprofloxacin-resistant isolates [ 120 – 123 ]. The fluorocycline eravacycline (TP-434) and glycylcycline tigecycline (family: tetracyclines) also appear to be effective against gonococci [ 124 , 125 ].…”

Section: Reviewmentioning

confidence: 99%

Current and future antimicrobial treatment of gonorrhoea – the rapidly evolving Neisseria gonorrhoeae continues to challenge

2015

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Neisseria gonorrhoeae has developed antimicrobial resistance (AMR) to all drugs previously and currently recommended for empirical monotherapy of gonorrhoea. In vitro resistance, including high-level, to the last option ceftriaxone and sporadic failures to treat pharyngeal gonorrhoea with ceftriaxone have emerged. In response, empirical dual antimicrobial therapy (ceftriaxone 250–1000 mg plus azithromycin 1–2 g) has been introduced in several particularly high-income regions or countries. These treatment regimens appear currently effective and should be considered in all settings where local quality assured AMR data do not support other therapeutic options. However, the dual antimicrobial regimens, implemented in limited geographic regions, will not entirely prevent resistance emergence and, unfortunately, most likely it is only a matter of when, and not if, treatment failures with also these dual antimicrobial regimens will emerge. Accordingly, novel affordable antimicrobials for monotherapy or at least inclusion in new dual treatment regimens, which might need to be considered for all newly developed antimicrobials, are essential. Several of the recently developed antimicrobials deserve increased attention for potential future treatment of gonorrhoea. In vitro activity studies examining collections of geographically, temporally and genetically diverse gonococcal isolates, including multidrug-resistant strains particularly with resistance to ceftriaxone and azithromycin, are important. Furthermore, understanding of effects and biological fitness of current and emerging (in vitro induced/selected and in vivo emerged) genetic resistance mechanisms for these antimicrobials, prediction of resistance emergence, time-kill curve analysis to evaluate antibacterial activity, appropriate mice experiments, and correlates between genetic and phenotypic laboratory parameters, and clinical treatment outcomes, would also be valuable. Subsequently, appropriately designed, randomized controlled clinical trials evaluating efficacy, ideal dose, toxicity, adverse effects, cost, and pharmacokinetic/pharmacodynamics data for anogenital and, importantly, also pharyngeal gonorrhoea, i.e. because treatment failures initially emerge at this anatomical site. Finally, in the future treatment at first health care visit will ideally be individually-tailored, i.e. by novel rapid phenotypic AMR tests and/or genetic point of care AMR tests, including detection of gonococci, which will improve the management and public health control of gonorrhoea and AMR. Nevertheless, now is certainly the right time to readdress the challenges of developing a gonococcal vaccine.

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“…The tetracycline derivatives, glycylcycline tigecycline and fluorocycline eravacycline (TP-434), have also been shown to be effective against ceftriaxone-resistant gonococci in vitro , yet, concerns remain regarding their usage and effectiveness 236237. Recently, new broad-spectrum fluoroquinolones, such as avarofloxacin (JNJ-Q2) 238, delafloxacin, sitafloxacin 239, and WQ-3810 240, have displayed high potency against multidrug-resistant gonococcal isolates in vitro including ciprofloxacin-resistant strains. Finally, the lipoglycopeptide dalbavancin and 2-acyl carbapenems, SM-295291 and SM-369926, are among potential antimicrobials that can be used in gonorrhea treatment to a limited extent 241.…”

Section: Molecular Epidemiology - a Historical Reviewmentioning

confidence: 99%

Gonorrhea – an evolving disease of the new millennium

Hill¹,

Masters²,

Wachter³

2016

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Etiology, transmission and protection: Neisseria gonorrhoeae (the gonococcus) is the etiological agent for the strictly human sexually transmitted disease gonorrhea. Infections lead to limited immunity, therefore individuals can become repeatedly infected. Pathology/symptomatology: Gonorrhea is generally a non-complicated mucosal infection with a pustular discharge. More severe sequellae include salpingitis and pelvic inflammatory disease which may lead to sterility and/or ectopic pregnancy. Occasionally, the organism can disseminate as a bloodstream infection. Epidemiology, incidence and prevalence: Gonorrhea is a global disease infecting approximately 60 million people annually. In the United States there are approximately 300, 000 cases each year, with an incidence of approximately 100 cases per 100,000 population. Treatment and curability: Gonorrhea is susceptible to an array of antibiotics. Antibiotic resistance is becoming a major problem and there are fears that the gonococcus will become the next “superbug” as the antibiotic arsenal diminishes. Currently, third generation extended-spectrum cephalosporins are being prescribed. Molecular mechanisms of infection: Gonococci elaborate numerous strategies to thwart the immune system. The organism engages in extensive phase (on/off switching) and antigenic variation of several surface antigens. The organism expresses IgA protease which cleaves mucosal antibody. The organism can become serum resistant due to its ability to sialylate lipooligosaccharide in conjunction with its ability to subvert complement activation. The gonococcus can survive within neutrophils as well as in several other lymphocytic cells. The organism manipulates the immune response such that no immune memory is generated which leads to a lack of protective immunity.

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In vitro activity of WQ-3810, a novel fluoroquinolone, against multidrug-resistant and fluoroquinolone-resistant pathogens

Cited by 24 publications

References 23 publications

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae : A Major Global Public Health Problem in the 21st Century

Antimicrobial Resistance Expressed by Neisseria gonorrhoeae : A Major Global Public Health Problem in the 21st Century

Current and future antimicrobial treatment of gonorrhoea – the rapidly evolving Neisseria gonorrhoeae continues to challenge

Gonorrhea – an evolving disease of the new millennium

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