MPA | Pharmacy News

By Jade L. Abudia, B.S., Pharm.D., PGY1 pharmacy resident, Aleda E. Lutz VA Medical Center, Saginaw and Caleb Divens, M.B.A., Pharm.D., PGY1 pharmacy resident, Aleda E. Lutz VA Medical Center, Saginaw

On June 19, 2017, Melinta Therapeutics announced approval of a new fluoroquinolone (FQ), Baxdela (delafloxacin), by the U.S. Food and Drug Administration (FDA).1 Delafloxacin was given priority review by the FDA due to its designation as a Qualified Infectious Disease Product (QIDP) which is incentivized by a five-year extension to any non-patent exclusivity period.2 New Drug Application (NDA) approvals were supported by two Phase 3 studies in patients with acute bacterial skin and skin structure infections (ABSSSI), demonstrating that IV and PO delafloxacin monotherapy was statistically non-inferior to the combination of vancomycin plus aztreonam at the FDA primary endpoint of early clinical response at 48-72 hours.3 

Delafloxacin was developed to be structurally different through the elimination of a basic group present in other FQs. This modification results in ionic characteristics that allow delafloxacin to pass into the bacterium easily; once inside, the charge characteristics change due to internal bacterium pH. The change causes delafloxacin to be ‘trapped’ inside the pathogen and translates to efficacy at much lower minimum inhibitory concentrations (MICs). MIC is used to determine antibiotic susceptibility and antimicrobials with excess exposure above the MIC have a reduced probability of selecting for resistant pathogens.3

Delafloxacin has activity against gram positive bacteria, gram negative bacteria, anaerobes and atypical bacteria.First and second generation FQs were primarily used in gram negative and atypical bacteria; further modifications led to the development of the third and forth generation FQs which exhibit improved gram positive coverage but increased occurrence of resistance development.5 Of these later generation FQs, moxifloxacin is largely considered the most potent gram-positive FQ. Delafloxacin exhibits a MIC two-to-four fold lower than those of moxifloxacin in gram positive bacteria.4 Interestingly, delafloxacin achieves this feat by the molecular alterations that allow for its accumulation within bacteria rather than by being a more potent topoisomerase inhibitor.3

Adverse effects with delafloxacin have shown to be dependent upon its dose. For its FDA-approved indication, delafloxacin is dosed at 300 mg IV every 12 hours or 450 mg PO every 12 hours for five to 14 days.6 The 450 mg tablet is bioequivalent to and interchangeable with the 300 mg IV dose, and can be dosed without regard to food. For both IV and PO administration, gastrointestinal adverse events were the most reported (nausea and diarrhea).7,8 There were two cases of elevated transaminase levels in a single comparative study.9 Presently, the only recommended dose adjustment is for IV use in patients with eGFR 15-29 mL/min/1.73 m2 who should receive 200 mg twice daily. There are no dose adjustments in the same eGFR range for PO dosing. Delafloxacin IV and PO formulations are not recommended in patients with eGFR <15 mL/min/1.73 m.2,6 The only interaction for delafloxacin that should be avoided is IV line co-administration with any solution containing multivalent cations, e.g., magnesium. Safety data, thus far, does not reveal any delafloxacin-specific adverse events, including prolongation of QTc interval or photosensitivity.3

While delafloxacin is currently FDA approved for ABSSSI, it is currently in other trials to expand its FDA-label approved indications. In respiratory infections, the possible use of delafloxacin in COPD exacerbations has been validated in a recent study comparing it with levofloxacin.4 In vivo, delafloxacin also exhibits especially low MICs against N. gonorrheae or H. pylori. In these cases, activity is expected to be even higher than in vivo, because of the acidic pH prevailing in the vagina or in the stomach. Sixty-five percent of a delafloxacin dose is unaltered when passed via urine; this high concentration of delafloxacin in the urine makes it an attractive option for E. coli or other enterobacteriaceae when involved in urinary tract infections.3 Most likely, the next indication for this drug will be community-acquired bacterial pneumonia (taking advantage of its very high potency on pneumococci and atypical pathogens) for which it was already granted as a QIDP by the FDA and is now in phase three trials.3,10

Considering delafloxacin’s broad spectrum of activity, structural advantages and metabolism, it has a multitude of potential. Safety data are reassuring but still preliminary and time is needed to assess the full implications of this promising but novel agent. 

References:
  1. Ernst D. New Antibiotic Baxdela Gets FDA Approval. MPR. http://www.empr.com/news/delafloxacin-acute-bacterial-skin-structure-infections-abssi-mrsa-melinta/article/669709/. Published June 20, 2017. Accessed July 29, 2017.
  2. Ligand’s Partner Melinta Therapeutics Announces U.S. FDA Approval of Baxdela™ (Delafloxacin) for Acute Bacterial Skin and Skin Structure Infections (ABSSSI). Business Wire. http://www.businesswire.com/news/home/20170620005605/en/. Published June 20, 2017. Accessed July 29, 2017.
  3. Bambeke FCAV. Delafloxacin, a non-zwitterionic fluoroquinolone in Phase III of clinical development: evaluation of its pharmacology, pharmacokinetics, pharmacodynamics and clinical efficacy. Future Microbiol. 2015;10(7):1111-1123. doi:10.2217/fmb.15.39.
  4. Candel FJ, Peñuelas M. Delafloxacin: design, development and potential place in therapy. Drug Des Dev Ther. 2017;11:881-891. doi:10.2147/dddt.s106071.
  5. Pradhan S. Topical Fluoroquinolones: Current Perspectives. Delhi Journal of Ophthalmology. 2015;25(4):267-271. doi:10.7869/djo.121.
  6. Baxdela [package insert]. Lincolnshire, IL: Melinta Therapeutics, Inc; 2017.
  7. Hoover R, Hunt T, Benedict M, et al. Safety, tolerability and pharma¬cokinetic properties of intravenous delafloxacin after single and multiple doses in healthy volunteers. Clin Ther. 2016;38(1):53–65.
  8. Hoover R, Hunt T, Benedict M, et al. Single and multiple ascending-dose studies of oral delafloxacin: effects of food, sex and age. Clin Ther. 2016;38(1):39–52.
  9. Kingsley J, Mehra P, Lawrence LE, et al. A randomized, double-blind, phase 2 study to evaluate subjective and objective outcomes in patients with acute bacterial skin and skin structure infections treated with delafloxacin, linezolid or vancomycin. J Antimicrob Chemother. 2016;71(3):821–829.
  10. Melinta Therapeutics, Inc. A phase 3, multicenter, randomized, double-blind, comparator-controlled study to evaluate the safety and efficacy of intravenous to oral delafloxacin in adult subjects with community-acquired bacterial pneumonia. Clinical Trials. https://clinicaltrials.gov/ct2/show/NCT02679573. NML Identifier: NCT02679573. Accessed March 15, 2017.

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