{"id":1254,"date":"2015-02-02T15:28:20","date_gmt":"2015-02-02T20:28:20","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1254"},"modified":"2015-07-11T11:57:05","modified_gmt":"2015-07-11T15:57:05","slug":"a-go-no-go-decision-delafloxacin-stumbles-in-gonorrhea-study","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/02\/02\/1254\/a-go-no-go-decision-delafloxacin-stumbles-in-gonorrhea-study\/","title":{"rendered":"A GO \/ NO GO decision:\u00a0 Delafloxacin Stumbles in Gonorrhea Study"},"content":{"rendered":"

The treatment history of N. gonorrhoeae makes for fascinating reading.\u00a0 This organism has always been able to keep the upper hand in the war of bug versus drug.\u00a0 Once susceptible to sulfa drugs, to penicillin, tetracyclines and fluoroquinolones, it sequentially become resistant in the matter of a decade to every class of drug.\u00a0 At one time it looked like the organism would become PCN-susceptible again but that hope did not really materialize.\u00a0 Hence, we are all a bit nervous about the time when ceftriaxone loses its efficacy.\"mic-2\"<\/a><\/p>\n

As cefixime resistance has slowly crept up and the drug is no longer an alternative to ceftriaxone, we are looking for a\u00a0new antibiotic\u00a0that can provide >95% efficacy, i.e., eradication, of genital gonorrhea with a single shot (or a single pill).\u00a0 This is a high bar for any antibiotic, no doubt, but this\u00a0is the hurdle applied by regulatory agencies.<\/p>\n

Now we hear that delafloxacin, a promising new fluroquinolone, did not make the grade:\u00a0 According to a recent press release, Melinta (formerly Rib-X) had to stop the Phase 3 gonorrhea study for reasons of \u201cinsufficient efficacy\u201d.[1]<\/a><\/p>\n

While this is disappointing news, it is also very unexpected news.\u00a0 The activity of delafloxacin against MDR N. gonorrhoeae isolates was studied extensively by Rib-X \/ Melinta.\u00a0 Delafloxacin and a panel of antibiotics (spectinomycin, ciprofloxacin, ceftriaxone, tetracycline, penicillin) were tested against 141 isolates from 2 institutions.\u00a0 Compared to ciprofloxacin, delafloxacin showed a very clear MIC separation, being many dilution steps more potent.\u00a0 More importantly, the MIC90 values for delafloxacin were very low, in the 0.125-0.5 mg\/L range.\u00a0 With a single oral dose, serum levels should be more than adequate for organisms in this and even higher MIC ranges.\"MIC\"<\/a><\/p>\n

So\u00a0why is there\u00a0\u201cinsufficient efficacy\u201d in a clinical study which presumably did\u00a0not enroll the worst pan-resistant GC patients\u00a0from Bangkok?\u00a0\u00a0 Has the susceptibility changed so much that isolates in 2014 are now much\u00a0more resistant than 6 years ago (2007-2010) when the surveillance microbiology study was done?\u00a0 \u00a0All this seems unlikely as FQ resistance is usually conferred by the gyrA or parC topoisomerase, which is mostly chromosomally mediated and multistep in nature. \u00a0Is a new quinolone-resistant strain at work here?<\/p>\n

This does not bode well for delafloxacin, a drug whose claim to fame is based on superior MIC data for MRSA.\u00a0 The recently completed\u00a0Phase 3 trial in ABSSSI seems to have met its non-inferiority\u00a0goals against vancomycin + aztreonam.\u00a0 Let\u2019s hope that there won\u2019t be a repeat of the GC experience with MRSA, the main differentiating feature of\u00a0delafloxacin.\u00a0 A NO GO for claps is a bitter disappointment, but a GO for MRSA is a must.\u00a0 Hopefully, efficacy against MRSA will hold up in clinical practice\u00a0and not turn out\u00a0short-lived as\u00a0with ciprofloxacin.[2]<\/a><\/p>\n

NOTE 1: It seems that the delafloxacin\u2019s QIDP designation is not in jeopardy as it was received for addressing the unmet need in GC and<\/span> for ABSSSI, the latter being the only indication left for Melinta to pursue.[3]<\/a><\/p>\n

NOTE 2: Solithromycin (Cempra) is a macrolide analogue currently in Phase 3 testing as a single dose treatment for uncomplicated gonorrhea.\u00a0 Phase 2 results were impressive: 22\/22 (100%) of evaluable patients were cured.[4]<\/a><\/p>\n

 <\/p>\n

References:
\n<\/strong>[1]<\/a> http:\/\/www.melinta.com\/news.php?c=41
\n[2]<\/a> H. Blumberg J Infect Dis. 1991 163:1279
\n[3]<\/a> http:\/\/www.melinta.com\/news.php?c=24
\n[4]<\/a> http:\/\/www.cempra.com\/common\/pdf\/abstracts\/Abstract_ECCMID%202013_Soli%20for%20gonorrhea_Oral%20Pres.pdf<\/p>\n","protected":false},"excerpt":{"rendered":"

The treatment history of N. gonorrhoeae makes for fascinating reading.\u00a0 This organism has always been able to keep the upper hand in the war of bug versus drug.\u00a0 Once susceptible to sulfa drugs, to penicillin, tetracyclines and fluoroquinolones, it sequentially become resistant in the matter of a decade to every Continue reading A GO \/ NO GO decision:\u00a0 Delafloxacin Stumbles in Gonorrhea Study<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1256,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[140,19,3],"tags":[81,403,211,336,265,821,822,816,819,42,236,5,814,223,181,599,812,83,817,813,820,162,182,818,468,815,141,263,48],"class_list":["post-1254","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-interesting_facts","category-qidp_antibiotic","category-the_news","tag-absssi","tag-antibiotic-blog","tag-azithromycin","tag-aztreonam","tag-cefixime","tag-cefoxitin","tag-cefpodoxime","tag-ceftriaxone","tag-cempra","tag-ciprofloxacin","tag-delafloxacin","tag-fda","tag-gonorrhea","tag-macrolide","tag-mdr","tag-melinta","tag-mic90","tag-mrsa","tag-multi-drug-resistant","tag-n-gonorrhoeae","tag-ofoxacin","tag-penicillin","tag-resistance","tag-rib-x","tag-solithromycin","tag-spectinomycin","tag-sulfonamide","tag-tetracycline","tag-vancomycin"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/02\/Delaflox-GO-slider.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-ke","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":3238,"url":"https:\/\/allphasepharma.com\/dir\/2017\/03\/21\/3238\/gc-therapy-shooting-stars\/","url_meta":{"origin":1254,"position":0},"title":"GC Therapy – \u00a0Shooting for the Stars","author":"Harald","date":"March 21, 2017","format":false,"excerpt":"Besides ceftriaxone (CTRIAX), cefixime and spectinomycin we have no other highly effective single-dose treatment regimens for urogenital GC. Failures of all 3 drugs have been described but remain rare, can be overcome with higher doses of CTRIAX (1 g instead of 250 mg IM) or with azithromycin combination therapy. Worse\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/GC-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/GC-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2017\/03\/GC-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1561,"url":"https:\/\/allphasepharma.com\/dir\/2015\/06\/17\/1561\/treating-gc-in-the-face-of-dwindling-antibiotic-options-2\/","url_meta":{"origin":1254,"position":1},"title":"Treating GC in the Face of Dwindling Antibiotic Options \u2013 (2)","author":"Harald","date":"June 17, 2015","format":false,"excerpt":"For GC antibiotics, the development path looks like a trip down the road less traveled, leading into some uncharted territory. Let\u2019s take Melinta\u2019s statement\u00a0[1] at face value according to which the single 900 mg dose of delafloxacin failed because of \"insufficient efficacy\". 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