HIV and ID Observations

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 gonorrhoeae, Bacteroides 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:

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

— Brad Spellberg (@BradSpellberg) June 28, 2017

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:

[youtube https://www.youtube.com/watch?v=0nkgw-4VB0M]