IDStewardship

Five Things To Know About Delafloxacin

Delafoxacin is a fluoroquinolone antibiotic that received FDA-approval in June 2017. In this article two infectious diseases pharmacists who recently authored a review article about delafloxacin identify five important things to know about it. 

Authored By: Wesley Kufel, PharmD, BCPS, AAHIVP and Bryan T. Mogle, PharmD, BCPS, AAHIVP

Dr. Kufel and Dr. Mogle are co-authors on a recently published delafloxacin review article in Journal of Antimicrobial Chemotherapy:

Fluoroquinolones (FQs) are one of the most commonly prescribed classes of antibiotics in the United States (US).1 Members of the FQ class such as ciprofloxacin, levofloxacin, and moxifloxacin are utilized in a variety of infectious disease states including, but not limited to respiratory tract infections, urinary tract infections, and bone and joint infections. There are many properties of FQs that make them appealing antibiotics for clinical use, including excellent oral bioavailability, distribution and penetration to various sites of infection, IV and PO dosing formulations, and broad spectrum of activity. However, FQs are often inappropriately overprescribed, which has led to the development of FQ-resistant bacteria.2  FQ use is also associated with several potential adverse effects and consequences including Clostridium difficile-associated diarrhea, tendonitis and tendon rupture, QTc prolongation and torsades de pointes, central nervous system effects, dysglycemia, and photosensitivity. The US Food and Drug Administration (FDA) issued a warning in 2016 stating that adverse effects associated with FQs outweigh the benefits in certain infections.3 Thus, antimicrobial stewardship programs commonly target FQ use to minimize inappropriate prescribing.

Delafloxacin (BaxdelaTM), a novel anionic FQ, was approved by the FDA on June 19th, 2017 for the indication of acute bacterial skin and skin structure infections (ABSSSI).

So, another FQ gains US FDA approval. The ABSSSI indication is not surprising since this has been the most common indication for antibiotics approved by the US FDA in the past ten years. Many infectious disease pharmacists and physicians may be wondering some of the following questions: How is delafloxacin any different than the other FQs currently available? Is another FQ truly needed? Where does delafloxacin potentially fit into clinical practice? To help begin to answer some of these questions, here we provide five things to know about delafloxacin…

1. A unique spectrum of activity

Delafloxacin is currently the only antibiotic with in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa.4 Yes, you heard that correctly, a FQ for MRSA? Delafloxacin exhibited at least a 64-fold lower MIC50 for MRSA compared to levofloxacin among isolates obtained from patients enrolled in Phase III studies, and retained activity against levofloxacin non-susceptible isolates. This is thought to be influenced by delafloxacin’s enhanced activity in acidic environments relative to other FQs. However, this may ring a bell that previous FQs (i.e. ciprofloxacin) demonstrated activity against MRSA, but resistance developed rather quickly after use in the clinical setting.5 Thus, it is unclear if delafloxacin will display activity against MRSA in the future.

The activity of delafloxacin against P. aeruginosa and other Gram-negative bacteria is similar to that of ciprofloxacin.6 Delafloxacin additionally has activity against certain anaerobic bacteria including in vitro activity against Bacteroides fragilis. Delafloxacin is also unique in that it is an anionic FQ, whereas other FQs are zwitterioinic. This basically means that delafloxacin has increased accumulation in bacteria allowing for enhanced bactericidal activity.

Table 1. General comparative in vitro activities of various FQs

Organism(s)

Delafloxacin

Ciprofloxacin

Levofloxacin

Moxifloxacin
Streptococcus pneumoniae

✔

✔

✔
MRSA

✔
P. aeruginosa

✔

✔

✔
Anaerobes

✔

✔
Atypicals

✔

✔

✔

✔

2. Where does delafloxacin fit into clinical practice?

This is a difficult question and you are likely to get different responses based on the clinician you ask.

There are currently no indications for which delafloxacin should be prescribed as a first-line treatment option due to the lack of clinical data supporting delafloxacin for various infectious disease states as well as the concerns regarding FQs in terms of adverse effects and resistance.7 We have tried to identify potential uses for delafloxacin, but these are largely hypothetical based on pharmacologic properties, clinical data, and our opinions:

  • Only FDA-approved for ABSSSI: However, due to the fact that the vast majority of ABSSSI are caused by Gram-positive bacteria, routine use of delafloxacin in this setting would likely provide unnecessary broad Gram-negative coverage and could increase the development of FQ resistance amongst Gram-negative organisms.
  • Potential for polymicrobial diabetic foot infections and osteoarticular infection: In scenarios where polymicrobial diabetic foot infections are suspected, current international guidelines recommend combining an anti-MRSA agent with another agent such as a FQ.8 Delafloxacin has the potential to consolidate treatment into single oral option and obviate the need for central venous catheter access, providing MRSA, P. aeruginosa, and anaerobic coverage all at once. Thus, delafloxacin would be an attractive option for transition from inpatient to outpatient management to avoid the need for IV antibiotics in the outpatient setting. Delafloxacin could also be expected to have similar bone penetration to other FQs and have utility in the treatment of osteomyelitis, however, no human data currently exist to confirm this notion. Lastly, because of delafloxacin’s ability to penetrate biofilms, this antibiotic could also play a role in the management of prosthetic joint infections where rifampin is often used, and poses less of a potential for drug-drug interactions.9
  • Potential step-down oral therapy for bloodstream infections: FQs are often used as sequential PO therapy following IV therapy in Gram-negative bacteremia,10 and less commonly, linezolid is used as sequential PO therapy in MRSA bacteremia.11 Because of delafloxacin’s spectrum of activity encompassing both MRSA and Gram-negative bacteria, this antibiotic has potential to be of use in these scenarios. In Phase III studies, a minority of patients treated with delafloxacin were also bacteremic, however, specific outcomes for these patients are not described. Thus, further data is needed in this area.
  • Demonstrated efficacy in obese patients: Investigator assessment of cure was found to be higher with delafloxacin compared to vancomycin plus aztreonam in obese patients in one Phase III trial,12 a finding that was also identified during a Phase II trial of delafloxacin compared to vancomycin alone in the treatment of ABSSSI.13
  • Potential for lower respiratory tract infections: Melinta Therapeutics, Inc. is seeking an additional FDA-approved indication for delafloxacin in the treatment of community-acquired bacterial pneumonia (CABP). An ongoing Phase III trial (DEFINE-CABP) is comparing delafloxacin with moxifloxacin or linezolid if MRSA is confirmed for the treatment of CABP.14 However, because of delafloxacin’s spectrum of activity and enhanced activity in acidic environments due to its anionic chemical structure, perhaps a more suitable role for delafloxacin would be for the management of hospital-acquired or ventilator associated pneumonia/empyema where multidrug-resistant organisms are more commonly found.
  • Need for long-term safety and resistance data: As with any new antibiotic, long-term safety and resistance data are needed. FQs are associated with many potential adverse effects, and several FQs have been withdrawn from the market due to post-marketing adverse event reporting. Similarly, development of resistance will also be a major concern as delafloxacin is introduced into clinical practice.

3. A promising antibiotic for gonorrhea infections is no more

Neisseria gonnorrheae resistance is increasing, and limited effective antibiotics are currently available for management. Delafloxacin demonstrated surprisingly low minimum inhibitory concentration (MIC) values against N. gonnorrheae based on in vitro studies, and appeared to be a promising novel agent for gonorrhea infections. Thus, delafloxacin was studied in the PROCEEDING trial, a phase III randomized controlled trial, comparing a single-dose of oral delafloxacin 900 mg to a single-dose of intramuscular ceftriaxone 250 mg for uncomplicated urogenital gonorrhea.15 This study was terminated early after an interim analysis concluded that a single dose of delafloxacin may not be sufficient to treat some patients.

4. Side effect profile and drug-drug interactions

As an antibiotic class, FQs are associated with a wide variety of potential adverse effects as previously described. However, delafloxacin does exhibit some differences in adverse effects compared to other FQs. In the pooled analysis of the Phase III studies, delafloxacin was well-tolerated overall and the most common adverse reactions reported were diarrhea, nausea, and infusion site extravasation.16 Only two (0.3%) delafloxacin-treated patients in Phase III studies developed Clostridium difficile infection.

QTc prolongation: FQs such as ciprofloxacin, levofloxacin, and moxifloxacin have previously been associated with QTc prolongation and corresponding arrhythmias. Interestingly, delafloxacin did not demonstrate QTc prolongation in phase III clinical trials. Delafloxacin was also not associated with a clinically meaningful effect on QTc interval compared to moxifloxacin in a randomized, double-blind, four-period crossover study of 52 healthy adults.17

Photosensitivity: FQs have traditionally been associated with photosensitivity that is often dose-dependent. In a phase I study, delafloxacin failed to demonstrate a phototoxic effect compared with lomefloxacin, which demonstrated moderate phototoxicity.18

Inactive ingredients leading to serum creatinine elevations: Certain IV antimicrobial agents such as voriconazole or isavuconazole contain solvent vehicles or other inactive ingredients that can lead to increases in serum creatinine, especially when the solvent vehicle accumulates in patients with renal impairment. IV delafloxacin contains the solvent vehicle sulphobutylether-B-cyclodextrin (SBECD) as an inactive ingredient, which may contribute to serum creatinine elevations in patients with renal impairment.19

Drug-drug interactions: Fewer drug-drug interactions have been identified for delafloxacin than other available FQs.7 At labeled doses, delafloxacin has no inhibitory effect on any CYP450 isoenzymes, but is a mild inducer of CYP3A4. The clinical significance of this effect on CYP3A4 is thought to be minimal. Delafloxacin is also a substrate of P-gp and BRCP in vitro, however, the clinical relevance of co-administration of delafloxacin with P-gp and/or BRCP inhibitors is unknown. Make sure you still appropriately space administration of delafloxacin and polyvalent cations to avoid chelation and reduced absorption!

5. Dosing considerations and costs

Delafloxacin is available in both oral and IV preparations.19 The oral formulation is available as 450 mg tablets and the IV formulation is available as a 300 mg solution for injection, both of which should be dosed twice daily. Unfortunately, delafloxacin is not as convenient in terms of dosing frequency as compared to levofloxacin and moxifloxacin, which are both administered once daily.

The oral delafloxacin formulation is a larger dose to account for the drug’s bioavailability of 58.8%, but both formulations provide equivalent exposure. The IV formulation should be administered over 60 minutes. In phase III studies, delafloxacin was typically administered between 5-14 days with a mean duration of 7 days. No dosage adjustment is necessary for patients with hepatic impairment, however, renal dose adjustments are required. Approximately 19% of IV delafloxacin was removed during hemodialysis, yet delafloxacin administration is not recommended for patients with end-stage renal disease or those on hemodialysis due to the lack of data in this patient population.

No surprise here…The average wholesale price (AWP) for a 10-day course of PO delafloxacin (20 tablets) and IV is $1,620.00 and $3,180.00, respectively. This is significantly more expensive than other generically available FQs and other commonly prescribed antibiotics. 

Wrap-up

Delafloxacin is a novel anionic FQ with a broader spectrum of activity compared to previously available FQs that includes MRSA, P. aeruginosa, and anaerobes. Delafloxacin appears to be well tolerated and have minimal potential for drug-drug interactions, however, FDA warnings to avoid FQ use due to the potential for adverse events when other agents may be utilized should still be applied to delafloxacin.

Although currently indicated for ABSSSI, optimal use scenarios for delafloxacin are yet to be defined by further clinical studies. Post-marketing safety and resistance surveillance will be crucial in identifying delafloxacin’s role in clinical practice. It sure will be interesting to see where delafloxacin is commonly used in clinical practice!

Disclosures: The authors report no conflicts of interest.

REFERENCES

  1. Linder JA, Huang ES, Steinman MA et al. Fluoroquinolone prescribing in the United States: 1995 to 2002. Am J Med 2005; 118: 259–68.
  2. Spellberg B, Guidos R, Gilbert D et al. The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Clin Infect Dis 2008; 46: 155–64.
  3. 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.
  4. McCurdy S, Lawrence L, Quintas M et al. In vitro activity of delafloxacin and microbiological response against fluoroquinolone-susceptible and nonsusceptible Staphylococcus aureus isolates from two Phase 3 studies of acute bacterial skin and skin structure infections. Antimicrob Agents Chemother 2017; Epub of ahead of print.
  5. Blumberg HM, Rimland D, Carroll DJ et al. Rapid development of ciprofloxacin resistance in methicillin-susceptible and -resistant Staphylococcus aureus. J Infect Dis 1991; 163: 1279–85.
  6. Pfaller MA, Sader HS, Rhomberg PR et al. In vitro activity of delafloxacin against contemporary bacterial pathogens fromthe United States and Europe, 2014. Antimicrob Agents Chemother 2017; 61: pii: e02609-16.
  7. Mogle BT, Steele JM, Thomas SJ, et al. Clinical review of delafloxacin: a novel anionic fluoroquinolone. J Antimicrob Chemother 2018; Epub ahead of print.
  8. Lipsky BA, Berendt AR, Cornia PB et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012; 54: e132–73.
  9. Siala W, Mingeot-Leclercq MP, Tulkens PM et al. Comparison of the antibiotic activities of daptomycin, vancomycin, and the investigational fluoroquinolone delafloxacin against biofilms from Staphylococcus aureus clinical isolates. Antimicrob Agents Chemother 2014; 58: 6385–97.
  10. Kutob LF, Justo JA, Bookstaver PB et al. Effectiveness of oral antibiotics for definitive therapy of Gram-negative bloodstream infections. Int J Antimicrob Agents 2016; 48: 498–503.
  11. Shorr AF, Kunkel MJ, Kollef M. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies. J Antimicrob Chemother 2005; 56: 923-9.
  12. 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: 3471–80.
  13. 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: 821–9.
  14. Melinta Therapeutics, Inc. Study to Compare Delafloxacin to Moxifloxacin for the Treatment of Adults with Community-Acquired Bacterial Pneumonia (DEFINE-CABP). NCT02679573. https://clinicaltrials.gov/ct2/show/NCT02679573.
  15. Melinta Therapeutics, Inc. Melinta Therapeutics Ceases Phase 3 PROCEEDING Study. http://melinta.com/melinta-therapeutics-ceases-phase-3-proceeding-study/.
  16. Center for Drug Evaluation and Research: Delafloxacin NDA Briefing. Reference ID: 4113514. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208610Orig1s000,208611Orig1s000Approv.pdf.
  17. 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: 3469–73.
  18. Ferguson J, Lawrence L, Paulson S et al. Assessment of phototoxicity potential of delafloxacin in healthy male and female subjects: a Phase 1 study. In: Proceedings of the Fifty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy with the International Society of Chemotherapy’s International Congress of Chemotherapy and Infection, San Diego, CA, USA, 2015. Poster F-1198a. American Society for Microbiology, Washington, DC, USA.
  19. Baxdela (delafloxacin) [Package Insert]. Lincolnshire, IL, USA: Melinta Therapeutics Inc; 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208610s000,208611s000lbl.pdf.

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