{"id":8406,"date":"2017-07-02T09:05:17","date_gmt":"2017-07-02T13:05:17","guid":{"rendered":"http:\/\/blogs.nejm.org\/hiv-id-observations\/?p=8406"},"modified":"2018-03-06T06:43:35","modified_gmt":"2018-03-06T11:43:35","slug":"delafloxacin-new-quinolone-approved-skin-infections-thats-not-really-needed","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/hiv-id-observations\/index.php\/delafloxacin-new-quinolone-approved-skin-infections-thats-not-really-needed\/2017\/07\/02\/","title":{"rendered":"Delafloxacin, a New Quinolone, Is Approved for Skin Infections — But That’s Not Where It’s Really Needed"},"content":{"rendered":"
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MRSA chasing ciprofloxacin, 1991. (Not drawn to scale.)<\/p><\/div>\n

The history of the fluoroquinolone antibiotics can be divided into four eras, alternating good news and bad:<\/p>\n

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  1. Ciprofloxacin is approved — it covers everything, and is\u00a0miraculous.<\/strong>\u00a0We’re talking some tough customers here.\u00a0Pseudomonas aeruginosa!<\/em>\u00a0Staphylococcus aureus!<\/em>\u00a0Neisseria gonorrhoeae!<\/em>\u00a0Plus, pretty much every gram negative causing urinary tract infections. There was no intravenous formulation initially, but that hardly mattered since it had great oral absorption. I remember as a resident seeing a patient with a polymicrobial diabetic foot infection in 1990 who was facing a long course of IV antibiotics — but instead went on ciprofloxacin orally at the suggestion of a brilliant ID consultant. As I said, miraculous.<\/li>\n
  2. Resistance to quinolones emerges — and quickly.<\/strong> Staph aureus<\/em>, especially MRSA, quickly became resistant to quinolones. Then Pseudomonas aeruginosa.<\/em> Then a host of other gram negatives urinary pathogens. Then gonorrhea. Then enteric infections. Plus, we learned ciprofloxacin never should have been approved for treatment of pneumonia to begin with — whether it was problems with poor pneumococcal activity, or inadequate lung penetration, or both, it clearly was a bad respiratory tract drug. Oh well, it was fun while it lasted!<\/li>\n
  3. Respiratory fluoroquinolones ride\u00a0to the rescue.<\/strong> Levofloxacin, moxifloxacin, and especially<\/em> trovafloxacin picked\u00a0up many\u00a0of the bugs that ciprofloxacin was missing. In case those weren’t\u00a0enough options, there was sparfloxacin and grepafloxacin and gatifloxacin and gemifloxacin too. All\u00a0had far greater gram positive coverage than ciprofloxacin, especially for streptococcal isolates. Moxifloxacin and trovafloxacin also covered anaerobes. Trovafloxacin was FDA approved for\u00a0no fewer than 14 indications<\/a><\/strong> — a world record! And while many predicted inevitable pneumococcal resistance with\u00a0the extraordinarily widespread use of these drugs, it never became that much of a problem. There was a rule on most medical services that every patient had to receive at least one dose of levofloxacin before discharge. (I made that up.)<\/li>\n
  4. TOXICITY<\/strong>.<\/em> All caps, italicized, and bolded, for a reason. Quinolones, it turns out, are not so safe after all. The FDA pulled trovafloxacin (hepatotoxicity), grepafloxacin (QT prolongation), sparfloxacin (photosensitivity), temafloxacin (hemolytic anemia\u00a0and allergies) and gatifloxacin (hypoglycemia) from the market for safety concerns. The few surviving\u00a0quinolones have the dreaded black box warning for\u00a0serious adverse effects. This describes\u00a0not only idiopathic tendon rupture, but\u00a0also\u00a0“disabling and potentially permanent serious side effects that … involve the tendons, muscles, joints, nerves, and central nervous system.”<\/a>\u00a0<\/strong>While in some patients these side effects are difficult to distinguish from the multitude of other causes of fatigue, poor concentration, and joint pain, there’s little doubt that quinolones are highly toxic to certain individuals. Potentially life-threatening QT prolongation and Clostridium difficile<\/em>\u00a0— two problems separate from the quinolone toxicity syndrome, but still serious — can be added to the mix. The toxicity profile is\u00a0bad enough that the FDA advised<\/a>, in 2016, to limit outpatient prescribing of quinolones to “those who do not have alternative treatment options,” a major action for this regulatory board.<\/li>\n<\/ol>\n

    Into this messy mix, and arguably against great odds, we now have a new fluoroquinolone — delafloxacin. It’s available in oral and intravenous formulations (both given twice daily), is FDA-approved for treatment of skin and soft-tissue infections<\/a> (based on the results of this study<\/a>), and most notably, has activity against both Pseudomonas aeruginosa<\/em> and Staph aureus,\u00a0<\/em>including MRSA.<\/p>\n

    In vitro, its coverage also includes\u00a0most coagulase negative staphylococci, enteric gram negative rods, respiratory pathogens, Neisseria gonorrhoeae<\/em>,\u00a0Bacteroides fragilis,\u00a0<\/em>and Mycobacterium tuberculosis.<\/em><\/p>\n

    Various reviews (here’s a good one<\/a>) will cite the fact that unlike most quinolones, which are zwitterionic, delafloxacin is anionic, leading to increased accumulation in bacteria. That certainly sounds impressive, and a quinolone with reliable anti-pseudomonal\u00a0and MRSA coverage currently does not exist.<\/p>\n

    However, coverage and biochemistry notwithstanding, we\u00a0might wonder why we need another\u00a0treatment for skin infections, especially with the toxicity profile of quinolones. Indeed, the FDA-approved medication guide<\/a>\u00a0for the drug\u00a0goes to great lengths to warn people about potential side effects.<\/p>\n

    There are two answers to this mystery. First, it’s easier to get FDA-approval for treatment of skin and soft-tissue infections than it is for other indications. Cue up your favorite low hanging fruit analogy.<\/p>\n

    Second, the drug\u00a0was given priority review by the FDA since it was\u00a0designated as a Qualified Infectious Disease Product (QIDP) under the Generating Antibiotic Incentives Now (GAIN) Act of 2012.\u00a0While this act encourages novel antibiotic drug development, these\u00a0approvals\u00a0can leave clinicians scratching their head about why the drug is available at all:<\/p>\n

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    Oh joy. Another MRSA skin drug. Will wonders never cease. I've had to update my table. Can anyone spot the trend? pic.twitter.com\/td4BPCFgAS<\/a><\/p>\n

    — Brad Spellberg (@BradSpellberg) June 28, 2017<\/a><\/p><\/blockquote>\n