{"id":1907,"date":"2015-09-03T12:38:37","date_gmt":"2015-09-03T16:38:37","guid":{"rendered":"http:\/\/allphasepharma.com\/dir\/?p=1907"},"modified":"2015-09-03T12:41:44","modified_gmt":"2015-09-03T16:41:44","slug":"mrsa-fluoroquinolones-an-interesting-bunch-playing-a-high-stakes-game","status":"publish","type":"post","link":"https:\/\/allphasepharma.com\/dir\/2015\/09\/03\/1907\/mrsa-fluoroquinolones-an-interesting-bunch-playing-a-high-stakes-game\/","title":{"rendered":"MRSA Fluoroquinolones \u2013 An Interesting Bunch Playing a High-Stakes Game"},"content":{"rendered":"

\"antiMRSA<\/a><\/p>\n

Fluoroquinolones (FQ) of the ofloxacin\/ciprofloxacin generation were mainly active against Gram-negative bacteria, distinguishing themselves as cidal IV\/PO drugs with high\u00a0potency\u00a0against most lactose- and non-lactose fermenters.\u00a0 They were excellent against problem pathogens like P. aeruginosa, had excellent efficacy\u00a0against Salmonellae, the Gonococcus and other Neisseriae, and you could count on them for coverage of atypicals like Chlamydia (now: Chlamydophila), Mycoplasma, Legionella and some more exotic bugs (e.g., Vibrio cholerae).\u00a0 There were so few holes in the spectrum that it was easier to recite the organisms not covered.\u00a0 Among the latter, MRSA was always a big wide gaping hole, pretty much from Day 1 on.<\/p>\n

Well, not exactly: The activity of ciprofloxacin against MSSA and MRSA was not bad when you review\u00a0the MIC ranges in several early publications (0.25-0.5 mg\/L)[1]<\/a>.\u00a0 The rapid development of resistance in a relatively short period of time (with MIC > 64 mg\/L), sometimes occurring in patients while on therapy, soon became a universal problem.\u00a0 Clearly, these older FQ did not do well at all in MSSA or MRSA infections.\u00a0 With the advent of the \u2018respiratory quinolones\u2019, like levofloxacin, moxifloxacin and gatifloxacin, the situation has not improved: while these drugs had demonstrably better activity against S. pneumoniae, none of them can be relied on for S. aureus infections.[2]<\/a>\u00a0

The development of high-level resistance in MRSA occurred fast – sometimes while patients were on therapy<\/span><\/p>\n<\/div><\/p>\n

More recent susceptibility studies for CA-MRSA show ciprofloxacin MIC90<\/sub> >32, with 77% of isolates resistant by CLSI criteria. [3]<\/a>\u00a0 Almer found that all resistant isolates had mutations in both the gyrA (DNA gyrase) and the grlA (topoisomerase IV) genes resulting in\u00a0aminoacid changes.\u00a0 The \u2018classical\u2019 gyrA mutation (Ser84-Leu) was the most prevalent.\u00a0 Similar findings apply to levofloxacin.<\/p>\n

This spectrum gap is significant; FQ compounds with good MSSA and MRSA activity would fill a great need as only linezolid can currently provide IV and PO coverage for these pathogens.\u00a0 In order to succeed, any new FQ has to show excellent activity against MRSA with various co-resistance patterns based on pathogenicity islands (mainly an issue in HA- MRSA), including ciprofloxacin-R strains.<\/p>\n

Here my list of FQs in development that claim activity against MRSA (your feedback is appreciated<\/span>):<\/p>\n

\"MRSA<\/a><\/p>\n

FM= Frequency of Mutation<\/span><\/em><\/p>\n

Given the history of rapid resistance development, it is not surprising that these purely MRSA compounds (they really have no other raison d\u2019etre<\/em> than reliably kill MRSA!) are being developed with much attention to bolster their MRSA claim.\u00a0 All MRSA FQ in the table have better MICs and lower spontaneous mutation rates than ciprofloxacin; unfortunately neither parameter is particularly predictive of the question at hand: Can they counted on to\u00a0provide reliable long-term anti-MRSA\u00a0 activity?

Q:\u00a0Can MRSA fluoroquinolones\u00a0provide reliable long-term anti-MRSA activity?<\/p>\n<\/div><\/p>\n

The MPC is a newer concept; it was developed to assess at which concentration single step mutations no longer occur.\u00a0 However, its clinical value has been challenged. [15]<\/a>\u00a0 It would be nice to predict resistance development based on microbiological data only, generated in the lab.\u00a0 But we are not there yet.<\/p>\n

To sum it up, clinical data proving that good MIC values translate into good clinical response rates without rapid development of resistance are still lacking.\u00a0 Even for the most advanced project, Delafloxacin, too little is known to gauge whether its MRSA activity will hold up.<\/p>\n

So, the jury is still out on which FQ is best against MRSA. But time will tell…<\/p>\n

\n

Abbreviations
\n<\/strong>PAE \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0post-antibiotic effect
\nMPC \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 mutation prevention concentration
\nFM \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0frequency of mutation
\nCLSI \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 Clinical Laboratory Standards Institute
\nCA-MRSA \u00a0 community-acquired MRSA
\nHA-MRSA \u00a0 hospital-acquired MRSA
\nFQ \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 \u00a0 fluoroquinolone<\/p>\n

References:
\n<\/strong>[1]<\/a> I Shalit, AAC 1989; 33: 593
\n[2]<\/a> H Blumberg,\u00a0 JID 1991;163:127
\n[3]<\/a> L Almer. Diagnostic Microbiology Infectious Disease 43: 2225; 2002
\n[4]<\/a> B Morrow. AAC\u00a0 55: 5512, 2011
\n[5]<\/a> J Remy.\u00a0 J Antimicrob Chemother. 2012; 67:2814
\n[6]<\/a> Goh ICAAC 2009, Abstract C1-1358
\n[7]<\/a> T Lauderdale Antimicrob Agents Chemother. 2010 Mar;54(3):1338
\n[8]<\/a> Expert Opin. Pharmacother. 16: 266; 2015
\n[9]<\/a> C Tsai Abstract L-1748b, ICAAC 2014: Meeting the Threat of Antibiotic Resistance: In Vitro Activity, Clinical Efficacy and Safety of Nemonoxacin, a Novel Non-Fluorinated Quinolone with QIDP Status
\n[10]<\/a> H Park. AAC 50: 2261, 2006
\n[11]<\/a> M Huband.\u00a0 AAC 59:\u00a0 467; 2015
\n[12]<\/a> S Bhagwat.\u00a0 AAC; 53: 811; 2009
\n[13]<\/a> S Bhagwat. AAC 50: 3568; 2006
\n[14]<\/a> F Schmitz.\u00a0 AAC 44: 3229, 2000
\n[15]<\/a> G Allen. Internat J Antimicrobial Agents 24; 2004: 150<\/p>\n","protected":false},"excerpt":{"rendered":"

Fluoroquinolones (FQ) of the ofloxacin\/ciprofloxacin generation were mainly active against Gram-negative bacteria, distinguishing themselves as cidal IV\/PO drugs with high\u00a0potency\u00a0against most lactose- and non-lactose fermenters.\u00a0 They were excellent against problem pathogens like P. aeruginosa, had excellent efficacy\u00a0against Salmonellae, the Gonococcus and other Neisseriae, and you could count on them for Continue reading MRSA Fluoroquinolones \u2013 An Interesting Bunch Playing a High-Stakes Game<\/span>→<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":1911,"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":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[3,18],"tags":[1197,292,1308,403,585,606,215,609,220,517,42,236,1314,1313,1306,469,287,1307,795,1164,213,214,72,599,600,47,1309,83,1311,1310,620,818,603,797,1210,624,623,605,1312,90],"class_list":["post-1907","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-the_news","category-the_viewpoint","tag-acorafloxacin","tag-actavis","tag-allergen","tag-antibiotic-blog","tag-astrazeneca","tag-avarofloxacin","tag-avelox","tag-azd-0914","tag-bayer","tag-cipro","tag-ciprofloxacin","tag-delafloxacin","tag-dong-wha","tag-dw-224a","tag-entasis","tag-finafloxacin","tag-forest","tag-furiex","tag-gatifloxacin","tag-jnj","tag-levofloxacin","tag-levoquin","tag-linezolid","tag-melinta","tag-merlion","tag-moxifloxacin","tag-mpc","tag-mrsa","tag-mutation-frequency","tag-mutation-prevention-concentration","tag-nemonoxacin","tag-rib-x","tag-taigen","tag-tequin","tag-tg-873870","tag-wck-2349","tag-wck-771","tag-wockhardt","tag-zabofloxacin","tag-zyvox"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2015\/09\/antiMRSA-1-copy.jpg?fit=640%2C180&ssl=1","jetpack_shortlink":"https:\/\/wp.me\/p4KWFr-uL","jetpack_sharing_enabled":true,"jetpack-related-posts":[{"id":1800,"url":"https:\/\/allphasepharma.com\/dir\/2015\/08\/01\/1800\/qidp-drugs-4th-edition\/","url_meta":{"origin":1907,"position":0},"title":"QIDP Drugs – 4th Edition","author":"Harald","date":"August 1, 2015","format":false,"excerpt":">>> For the latest QIDP list, please click HERE \u00a0<<< Since our\u00a0last QIDP blog from April 8, 2015, several new drugs have made the list which now includes 41 compounds. 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In addition, researchers\u00a0mention a peculiar MoA for this gyrase\/topoisomerase\u2026","rel":"","context":"In "QIDP Antibiotics"","block_context":{"text":"QIDP Antibiotics","link":"https:\/\/allphasepharma.com\/dir\/category\/qidp_antibiotic\/"},"img":{"alt_text":"gonorrhea - slider","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/05\/gonorrhea-slider.jpg?resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/05\/gonorrhea-slider.jpg?resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2016\/05\/gonorrhea-slider.jpg?resize=525%2C300 1.5x"},"classes":[]},{"id":1385,"url":"https:\/\/allphasepharma.com\/dir\/2015\/04\/21\/1385\/an-inconvenient-truth-ciprofloxacin-resistant-campylobacter\/","url_meta":{"origin":1907,"position":3},"title":"An Inconvenient Truth: Ciprofloxacin-Resistant Campylobacter","author":"Harald","date":"April 21, 2015","format":false,"excerpt":"When Al Gore became a best-selling author with \u201cAn Inconvenient Truth\u201d he warned about climate change.\u00a0 When it comes to antibiotic resistance and the current situation of \u201cBad Bugs, No Drugs\u201d, there are many voices warning us about a return to the pre-antibiotic era. 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This substance, when combined with meropenem, restored antibiotic activity against an NDM lab strain.\u00a0 \u00a0AMA is a substance which was already tested in the past in humans.\u00a0 Concerns about interference with human metalloenzymes proved\u2026","rel":"","context":"In "Recent Literature"","block_context":{"text":"Recent Literature","link":"https:\/\/allphasepharma.com\/dir\/category\/recent_literature\/"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/09\/NewLit-slider-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200","width":350,"height":200,"srcset":"https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/09\/NewLit-slider-copy.jpg?fit=640%2C200&ssl=1&resize=350%2C200 1x, https:\/\/i0.wp.com\/allphasepharma.com\/dir\/wp-content\/uploads\/2014\/09\/NewLit-slider-copy.jpg?fit=640%2C200&ssl=1&resize=525%2C300 1.5x"},"classes":[]},{"id":2095,"url":"https:\/\/allphasepharma.com\/dir\/2015\/11\/03\/2095\/amdac-november-5-2015-on-fluoroquinolones-in-as-aecb-uuti-part-1\/","url_meta":{"origin":1907,"position":5},"title":"AMDAC November 5, 2015 on Fluoroquinolones in ABS, ABECB, uUTI\u00a0 – Part 1","author":"Harald","date":"November 3, 2015","format":false,"excerpt":"Only now, a few days before the actual AMDAC meeting, the\u00a0FDA\u2019s Briefing Document becomes available to the public.\u00a0 The topic of the December 5th meeting:\u00a0 Reappraisal of the risk\/benefit of fluoroquinolones (FQ) in approved but \u201cmild, self-limiting\u201d disease indications in light of new post-approval safety issues. 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