July 2nd, 2017

Delafloxacin, a New Quinolone, Is Approved for Skin Infections — But That’s Not Where It’s Really Needed

MRSA chasing ciprofloxacin, 1991. (Not drawn to scale.)

The history of the fluoroquinolone antibiotics can be divided into four eras, alternating good news and bad:

  1. Ciprofloxacin is approved — it covers everything, and is miraculous. We’re talking some tough customers here. Pseudomonas aeruginosa! Staphylococcus aureus! Neisseria gonorrhoeae! Plus, 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.
  2. Resistance to quinolones emerges — and quickly. Staph aureus, especially MRSA, quickly became resistant to quinolones. Then Pseudomonas aeruginosa. 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!
  3. Respiratory fluoroquinolones ride to the rescue. Levofloxacin, moxifloxacin, and especially trovafloxacin picked up many of the bugs that ciprofloxacin was missing. In case those weren’t enough options, there was sparfloxacin and grepafloxacin and gatifloxacin and gemifloxacin too. All had far greater gram positive coverage than ciprofloxacin, especially for streptococcal isolates. Moxifloxacin and trovafloxacin also covered anaerobes. Trovafloxacin was FDA approved for no fewer than 14 indications — a world record! And while many predicted inevitable pneumococcal resistance with the 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.)
  4. TOXICITY. 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 and allergies) and gatifloxacin (hypoglycemia) from the market for safety concerns. The few surviving quinolones have the dreaded black box warning for serious adverse effects. This describes not only idiopathic tendon rupture, but also “disabling and potentially permanent serious side effects that … involve the tendons, muscles, joints, nerves, and central nervous system.” 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 — two problems separate from the quinolone toxicity syndrome, but still serious — can be added to the mix. The toxicity profile is bad enough that the FDA advised, in 2016, to limit outpatient prescribing of quinolones to “those who do not have alternative treatment options,” a major action for this regulatory board.

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 (based on the results of this study), and most notably, has activity against both Pseudomonas aeruginosa and Staph aureus, including MRSA.

In vitro, its coverage also includes most coagulase negative staphylococci, enteric gram negative rods, respiratory pathogens, Neisseria gonorrhoeaeBacteroides fragilis, and Mycobacterium tuberculosis.

Various reviews (here’s a good one) 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 and MRSA coverage currently does not exist.

However, coverage and biochemistry notwithstanding, we might wonder why we need another treatment for skin infections, especially with the toxicity profile of quinolones. Indeed, the FDA-approved medication guide for the drug goes to great lengths to warn people about potential side effects.

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.

Second, the drug was given priority review by the FDA since it was designated as a Qualified Infectious Disease Product (QIDP) under the Generating Antibiotic Incentives Now (GAIN) Act of 2012. While this act encourages novel antibiotic drug development, these approvals can leave clinicians scratching their head about why the drug is available at all:

Ever the optimist, I’m hopeful that now that delafloxacin is approved, we will eventually see studies documenting its efficacy in clinical settings of greater unmet need.

Based on this search, it looks like trials in community-acquired pneumonia (ho-hum) and gonorrhea (good) are in the works. (The gonorrhea study was stopped — see comment below.)

Here are a few more study ideas, with admittedly much tougher patient populations and study endpoints, but leveraging delafloxacin’s antibacterial spectrum, bactericidal activity, and excellent oral bioavailability:

  • A randomized, phase 3 clinical trial comparing oral delafloxacin with intravenous vancomycin or daptomycin for Staph aureus bacteremia. Randomization would occur after clearance of blood cultures. Stratify based on MRSA vs MSSA.
  • A randomized, phase 3 clinical trial comparing oral delafloxacin with intravenous therapy in treatment of spinal osteomyelitis due to susceptible organisms. Randomization after stable on IV therapy. Stratify based on risk factor (injection drug use vs other) and causative organism (MRSA vs other).
  • A randomized, phase 3 clinical trial comparing oral delafloxacin with intravenous therapy in diabetic foot infections. Stratify based on whether the study subjects underwent surgical debridement.
  • A randomized, phase 3 clinical trial comparing oral delafloxacin with intravenous ertapenem or cefepime for treatment of complicated urinary tract infections due to resistant gram-negative organisms. Stratify based on Pseudomonas aeruginosa vs other.

So that’s 4 tough areas of ID practice to start. But why stop there? How about looking at delafloxacin in studies of MDR tuberculosis? Or non-tuberculous mycobacteria? Many interesting possibilities.

Ready to enroll?

And though totally unrelated, this made me laugh:

 

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11 Responses to “Delafloxacin, a New Quinolone, Is Approved for Skin Infections — But That’s Not Where It’s Really Needed”

  1. Brandon Dionne says:

    Unfortunately the gonorrhea phase 3 trial was terminated because the single dose wasn’t effective enough despite seemingly low MICs.

    • Paul Sax says:

      Thanks for this information, Brandon. Have amended the post.
      Paul

    • David Palm says:

      Hmmm. I’m all for the single-dose cure (particularly when measured against other single-administration generic drugs in hard-to-treat populations) but I have to wonder if a multiday course would’ve worked just as well and still be an effective reserve drug? I suppose there’s always off-label…?

  2. Loretta S says:

    At least the dog didn’t howl and politely sat down to enjoy the show.

    Thanks for the update on the new quinolone, Paul. I will await the inevitable reports of (a) heretofore unthought-of adverse effects and/or (b) resistance by some of the bacteria it currently is active against.

  3. Tim Gauthier says:

    Great article!… They say don’t be the first to use an antibiotic b/c you risk unknown toxicity & don’t be the last to use an antibiotic b/c the bacteria will probably be resistant by then…. I feel like this is a stronger warning than ever with a new FQ!… other thought on this topic is curiousity about how it might be priced. Hopefully less than $500 per day… we will see very soon!

  4. Sanjat Kanjilal says:

    Thanks for that nice historical perspective! I’m not optimistic that delafloxacin is a useful addition to our treatment toolbox for S.aureus, though I suppose it’s reasonable to withhold judgment until more epidemiologic data accumulates. In particular, it’s worth seeing if the greater intracellular accumulation relative to other quinolones would modify the barrier to resistance, which is quite low.

    A (now 26 year old) study showed the introduction of ciprofloxacin into a hospital formulary led to an increase in high level resistance in MRSA from 0% to 79% in just one year. Interestingly, among MSSA, resistance plateau’d at around 14% (PMID: 2037793). This study was done prior to modern typing techniques and suggested that resistance was acquired in multiple genetic backgrounds. Newer genomic epidemiology work (DOI: 10.1128/mBio.02183-15. and DOI: 10.1128/mBio.00054-15) has suggested that appearance of quinolone resistance in the mid-90s preceded the expansion and dominance of the CA-MRSA lineage USA-300. In our own hospital in Boston, we have found that quinolone resistance is highly associated with nosocomial lineages.

    All of this suggests (as you mention above) that the selective pressure of quinolones expands the niche for MRSA relative to other S. aureus subtypes and since these quinolones are not typically used to treat MRSA, this is likely a bystander effect. Given the increased morbidity and costs of treating patients with MRSA, I’d be highly cautious in expanding use of any quinolone for any indication.

    That being said, the bacteremia and complicated UTI trials you suggest could be interesting. I would anticipate showing efficacy of delafloxacin in DFI and osteomyelitis would be more problematic, particularly if debridement isn’t able to remove the entirety of a biofilm.

  5. It is curious that it took over 30 years for the toxicity of ciprofloxacin and other fluoroquinolones to be widely recognized, especially since the toxicity now rates a black box warning. There may be a message there.

  6. Jake says:

    Thanks very much Paul. You could imagine mechanisms where public funds could be shared with these small companies to do trials with clinically relevant outcomes early in a needed drug’s lifespan. Definitely some risk to them if their drug underperforms, but big reward too if the ID community felt more comfortable, earlier, adopting their new drug more widely.

  7. Sam S says:

    I am not sure this drug would be even be a useful addition for complicated urinary tract infections. Despite its mechanistic differences, delafloxacin MIC90s for quinolone resistant gram-negatives don’t seem very impressive. A recent study of isolates from the United States and Europe in AAC found that over 90% of fluoroquinolone resistant gram-negatives had decreased susceptibility to delafloxacin, and ciprofloxacin was still the most active fluoroquinolone against Pseudomonas (n = 200).
    doi: 10.1128/AAC.02609-16

  8. Cathy says:

    Great write-up and questions. My Achilles tendons will never forgive me for the course of quinolones I took 10+ years ago.

  9. Dave Berkowitz says:

    Agree, drug companies need to stop studying skin infections for new MRSA treatments. This drug will never be used for skin/soft tissue infections inpatient because it hits our DRG. Also, there are less broad spectrum options. Outpatient wise, insurance companies won’t ever cover it outside of the FDA approved indications. Same thing goes for Dalbavancin/Oritavancin. If either of those drugs had the FDA approval for disseminated infections like endocarditis, they’d be blockbuster drugs.

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

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