Do We Really Need Another Fluoroquinolone?

My how times change!  Fluoroquinolones, once considered a powerhouse over bacterial infections, now are basically blacklisted due to significant post-marketing identified adverse events and the development of fluoroquinolone resistant bacteria.  The US Food and Drug Administration (FDA) in 2006 issued a warning to providers that the adverse events associated with fluoroquinolone pharmacotherapy likely outweigh any benefit ascribed to this therapy in many common infectious disease states.¹  Given these safety issues, at least 7 oral and parenteral fluoroquinolones have been withdrawn from the Unites States market.  Many of these adverse reactions are well known to medical practitioners: tendinitis and tendon rupture, hepatic toxicity, QT prolongation, and dysglycemia, but recently the FDA is now requiring the manufacturers of fluoroquinolones to also warn about risk of aortic dissection or aneurism, as well as, potential mental health issues that may arise with the use of these antibiotics.^2-3

Then on June 19^th, 2017 a new novel fluoroquinolone (delafloxacin) was approved by the FDA for acute bacterial skin and skin structure infections (ABSSSI).  It is now available in both oral and IV preparations. So why now is another fluoroquinolone being brought to the market and is it any different from the 25 or so previous formulations of this class?  The answer is actually yes, I do however, say this with some trepidation after practicing in the days of trovafloxacin. 

Delafloxacin is a fluorinated quinolone, however unlike the other agents in this class, it is weakly acidic due to the lack of a basic group next to the fluorinated ring.  By changing these substitutions, it has resulted in a fluoroquinolone with a markedly increased spectrum of activity, improved cellular penetration, and significantly lower minimum inhibitory concentrations (MICs) under low pH conditions such as those found in abscesses.^4-5  Its mechanism of action is the same as any other fluroquinolone and displays concentration dependent killing.  However, potential game changers do exist for this drug.  It has a very broad spectrum of activity including nosocomial and atypical pathogens.^4-5  Delafloxacin has FDA approved breakpoints (i.e., susceptibility criteria) for many Gram-positive pathogens including MRSA.⁴  Yes, you heard that right, MRSA! Delafloxacin also continues to have activity against most of the clinically important gram-negative pathogens as previous fluoroquinolones, such as ciprofloxacin and levofloxacin, which includes Pseudomonas aeruginosa and Acinetobacter species. In vitro activity also has been demonstrated against Bacteroides fragilis and other anaerobic bacteria as well as atypical pathogens.^4-5  

Approval of delafloxacin was based on the PROCEED studies which were two phase III, multicenter, multinational double-blind, non-inferiority clinical trials that included a total of more than 1500 patients with ABSSSIs.^6-7  The first trial randomized patients to receive either delafloxacin 300 mg IV or vancomycin 15 mg/kg IV plus aztreonam IV twice daily.  The overall response rates at 48 to 72 hours were 78.2% and 80.9% in the delafloxacin and vancomycin plus aztreonam groups, respectively.⁶  The second trial randomized patients to delafloxacin 300 mg IV every 12 hours for 6 doses, then delafloxacin 450 mg PO every 12 hours versus Vancomycin 15 mg/kg IV plus Aztreonam 2 g IV q12h, and again clinical response rates at 48 to 72 hours was 83.7% for Delafloxacin and 80.6% for vancomycin plus aztreonam.⁷ 

Similar to other fluoroquinolone antibiotics, the most common adverse effects of delafloxacin occurring during clinical trials were associated with the gastrointestinal tract and included nausea, diarrhea, and vomiting.  However, there may be some curious differences, delafloxacin appears to not have any clinically relevant effect on the QTc interval, nor did it produce significant phototoxic potential when administered to healthy volunteers and compared to other fluoroquinolones.^8-9  However, other adverse effects frequently attributed to fluoroquinolones have not been determined at this time and will require extensive post-marketing surveillance to determine whether or not delafloxacin is any safer than the agents that came before it.  When considering drug-drug interactions, very few have been determined. It does not appear to inhibit any of the cytochrome P450 isoenzymes and only mildly induces cytochrome P450 3A4, the effect of which is considered to be negligible. Delafloxacin is also a substrate of P-glycoprotein and BCRP in vitro, however the significance of this remains to be elucidated.  As with all fluoroquinolones, separation from administered polyvalent cations should be performed to avoid chelation and reduction in absorbed dose.⁵

So, the question at hand is “do we really need another fluoroquinolone?” and in my opinion the answer is “maybe.”  It certainly is a very broad-spectrum antimicrobial, however it is only currently indicated for complicated skin/skin structure infections, however due to enhanced potency in acidic environments, as well as, activity against anaerobic pathogens, this agent may prove to be very effective as single drug therapy in pneumonia, complicated UTIs, decubitus ulcers, and intrabdominal infections (future ongoing trials will tell).  It certainly is not a first line agent for its current indication.  One area that is of interest to me is that of treating prosthetic joint infections in which material is retained.  It appears that delafloxacin has activity against Staph aureus biofilms in vitro and if proven successful in clinical trials could represent potential monotherapy for these infections and not having to use rifampin.⁵  So time will tell if delafloxacin proves to be a safe addition to our current antimicrobial arsenal against the increasing issue of bacterial resistance, especially MRSA. 

As always, I would love to hear from clinical pharmacists with experience using this new agent and what their personal findings have been.

Randolph V. Fugit, PharmD, BCPS is an internal medicine/infectious diseases clinical specialist and director, antimicrobial stewardship program, at the VA Rocky Mountain Regional Health Care System and clinical associate professor at the Skaggs School of Pharmacy & Pharmaceutical Sciences at the University of Colorado.

References:

1. FDA Drug Safety Communication: FDA Advises Restricting Fluoroquinolone Antibiotic Use for Certain Uncomplicated Infections; Warns about Disabling Side Effects that can Occur Together. https://www.fda.gov/Drugs/DrugSafety/ucm500143.htm. Accessed January 15, 2019.
2. FDA Drug Safety Communication: FDA warns about increased risk of ruptures or tears in the aorta blood vessels with fluoroquinolone antibiotics in certain patients. https://www.fda.gov/Drugs/DrugSafety/ucm628753.htm. Accessed January 15, 2019.
3. FDA Drug Safety Communication: FDA reinforces safety information about serious low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes. https://www.fda.gov/Drugs/DrugSafety/ucm611032.htm. Accessed January 15, 2019
4. Cho JC, Crotty MP, White BP, et al. What is old is new again: delafloxacin, a modern fluoroquinolone. Pharmacotherapy 2018;38:108-21.
5. Mogle BT, Steele JM, Thomas, et al. Clinical review of delafloxacin: a novel anionic fluoroquinolone. J Antimicrob Chemother 2018;73:1439-51.
6. Pullman J, Gardovskis J, Farley B, et al. Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a phase 3, double-blind, randomized study. J Antimicrob Chemother 2017;72:3471–3480.
7. Riordan WO, McManus AM, Teras J, et al. A comparison of the efficacy and safety of intravenous followed by oral delafloxacin with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections: a phase 3, multinational, double-blind, randomized study. Clin Infect Dis 2018:67:657-66.
8. Litwin JS, Benedict MS, Thorn MD, et al. A thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization. Antimicrob Agents Chemother 2015;59:3469–3473.
9. Ferguson J, Lawrence L, Paulson S, et al. Assessment of phototoxicity potential of delafloxacin in healthy male and female subjects: a phase I study [poster 1198]. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy 2015. San Diego, CA, USA, September 17–21, 2015.
10. Mogle, BT, Steele JM, Thomas SJ, et al. Clinical review of delafloxacin: a novel anionic fluoroquinolone. J Antimicrob Chemother. 2018;73:1439-51.