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Expert Review of Anti-infective Therapy
ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: http://www.tandfonline.com/loi/ierz20
Delafloxacin: a novel fluoroquinolone with activityagainst methicillin-resistant Staphylococcusaureus (MRSA) and Pseudomonas aeruginosa
Eric R. Ocheretyaner & Tae Eun Park
To cite this article: Eric R. Ocheretyaner & Tae Eun Park (2018): Delafloxacin: anovel fluoroquinolone with activity against methicillin-resistant Staphylococcus aureus(MRSA) and Pseudomonas aeruginosa, Expert Review of Anti-infective Therapy, DOI:10.1080/14787210.2018.1489721
To link to this article: https://doi.org/10.1080/14787210.2018.1489721
Accepted author version posted online: 18Jun 2018.
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Publisher: Taylor & Francis
Journal: Expert Review of Anti-infective Therapy
DOI: 10.1080/14787210.2018.1489721
Drug profile
Delafloxacin: a novel fluoroquinolone with activity against methicillin-resistant Staphylococcus
aureus and Pseudomonas aeruginosa
TITLE Delafloxacin: a novel fluoroquinolone with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa AUTHORS Eric R. Ocheretyaner1,2, and Tae Eun Park3,4 1Division of Pharmacy Practice, LIU Pharmacy (Arnold & Marie Schwartz College of Pharmacy and Health
Sciences), Brooklyn, New York, USA 2Department of Pharmacy, Kings County Hospital Center Brooklyn, New York, USA 3Division of Pharmacy Practice, Touro College of Pharmacy, New York, New York USA 4Department of Pharmacy, SUNY Downstate Medical Center, Brooklyn, New York USA FIRST AND CORRESPONDING AUTHOR Eric R. Ocheretyaner, PharmD, BCPS Assistant Professor of Pharmacy Practice LIU Pharmacy (Arnold & Marie Schwartz College of Pharmacy and Health Sciences) Brooklyn, New York 11201 Email: [email protected] ABSTRACT Introduction: The resistance to current antimicrobial agents, including fluoroquinolones, has continued to grow among various pathogens indicating a need for new antimicrobials to combat multi-drug resistant (MDR) organisms. In June 2017, delafloxacin received approval by the United States Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults caused by designated susceptible bacteria. Areas covered: This review describes the pharmacology, pharmacodynamics, pharmacokinetics, product information, efficacy, and safety of delafloxacin. Expert commentary:
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Delafloxacin is a novel oral and intravenous fluoroquinolone with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, offering a new option for the treatment of ABSSSI and potentially for complicated urinary tract infections and severe community-acquired bacterial pneumonia. Key words: Delafloxacin, Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, MRSA, fluoroquinolone
Eric R. Ocheretyaner1,2, and Tae Eun Park3,4 1Division of Pharmacy Practice, LIU Pharmacy (Arnold & Marie Schwartz College of Pharmacy and Health
Sciences), Brooklyn, New York, USA 2Department of Pharmacy, Kings County Hospital Center Brooklyn, New York, USA 3Division of Pharmacy Practice, Touro College of Pharmacy, New York, New York USA 4Department of Pharmacy, SUNY Downstate Medical Center, Brooklyn, New York USA
*Corresponding author
Eric R. Ocheretyaner
Assistant Professor of Pharmacy Practice
LIU Pharmacy (Arnold & Marie Schwartz College of Pharmacy and Health Sciences)
Brooklyn, New York 11201
Email: [email protected]
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ABSTRACT
Introduction: The resistance to current antimicrobial agents, including fluoroquinolones, has continued
to grow among various pathogens indicating a need for new antimicrobials to combat multi-drug
resistant (MDR) organisms. In June 2017, delafloxacin received approval by the United States Food and
Drug Administration for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in
adults caused by designated susceptible bacteria.
Areas covered: This review describes the pharmacology, pharmacodynamics, pharmacokinetics, product
information, efficacy, and safety of delafloxacin.
Expert commentary: Delafloxacin is a novel oral and intravenous fluoroquinolone with activity against
methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, offering a new option
for the treatment of ABSSSI and potentially for complicated urinary tract infections and severe
community-acquired bacterial pneumonia.
Key words: Delafloxacin, Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, MRSA,
fluoroquinolone
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1. INTRODUCTION AND OVERVIEW OF THE MARKET
The prevalence of bacterial resistance to currently available antibiotics continues to rise, and
therapeutic options are becoming limited [1]. The United States (US) Center for Disease Control and
Prevention (CDC) estimates a total of approximately 2 million illnesses are due to multi-drug resistant
(MDR) microorganisms leading to 23,000 deaths annually [2]. The ESKAPE pathogens (i.e. Enterococcus
faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas
aeruginosa, and Enterobacter spp.) pose the greatest threat with regards to resistance to most available
antibiotics; therefore, new antibiotic agents are needed. Amongst many MDR pathogens, methicillin-
resistant Staphylococcus aureus (MRSA) is of concern given its prevalence as well as its limited oral
treatment options. The oral treatments currently available for MRSA infections, with varying
susceptibility, are clindamycin, linezolid, sulfamethoxazole/trimethoprim, tedizolid, and tetracyclines,
none of which have activity against a MDR pathogen such as P. aeruginosa.
The quinolones were first developed in the 1960s, including nalidixic acid, cinoxacin, and oxolinic
acid. Addition of fluorine to quinolones yielded fluoroquinolones such as ofloxacin, ciprofloxacin,
norfloxacin, pefloxacin, levofloxacin, moxifloxacin, gatifloxacin, and gemifloxacin. The substituents
added to certain parts of the quinolone ring (e.g. fluorine) led to an increase in the potency of
antibacterial agents. The fluoroquinolones exhibit the antibacterial effects through inhibition of
bacterial topoisomerase IV and DNA gyrase (topoisomerase II) enzymes. Quinolones function as a
cellular poison by stabilizing the enzyme-DNA complexes after strand breakage, which the cell is able to
repair poorly. Therefore, quinolones bind to the DNA gyrase and DNA complex rather than the DNA
gyrase alone. The primary mechanism of resistance to fluoroquinolones is alteration in the primary
target enzyme of the fluoroquinolones; however, active efflux pumps can also be observed decreasing
the fluoroquinolone susceptibility [1]. There has been a focus to identify new fluoroquinolones to
combat the growing resistance. Several other fluoroquinolones currently in the pipeline are
avarofloxacin (JNJ-Q2), delafloxacin (WQ-3034), finafloxacin (BAY35-3377), zabofloxacin (DW224a), and
non-fluorinated nemonoxacin (TG-873870) [3].
In June 2017, delafloxacin (BaxdelaTM; Melinta Therapeutics, Inc.) received approval by the US
Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure
infections (ABSSSIs) in adults caused by designated susceptible bacteria [4]. The recommended dose of
delafloxacin for ABSSSIs is 300 mg intravenous (IV) infusion over one hour every 12 hours or 450 mg
orally every 12 hours for a total duration of five to 14 days. At the discretion of the provider, patients
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may be initiated on IV therapy and transitioned to oral therapy to complete the course of treatment.
Patients with renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2)
require a modification in the IV dose only (Table 3). Currently, there is insufficient information to
provide a dosing recommendation for patients that are receiving hemodialysis (HD) [4]. The objective of
this article is to review the pharmacological profile of delafloxacin as well as discuss the currently
available clinical trial data.
2. INTRODUCTION TO THE DRUG
2.1 Chemistry
The chemical structure of delafloxacin is 1-Deoxy-1-(methylamino)-D-glucitol, 1-(6-amino-3,5-
difluoropyridin-2-yl)-8-chloro-6-fluro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-
carboxylate (meglumine salt) (Figure 1). Delafloxacin has greater antibacterial properties compared to
other fluoroquinolones due to three structural differences: (1) large shape, which is driven by a
heteroaromatic substitution at N1, (2) unique polarity in quinolone nucleus, which is driven by presence
of two electron-withdrawing groups at C6 and C8, and (3) an anionic character at neutral pH, which is
driven by the lack of a basic substitution at C7. The large shape and polarity are the driving factors in
the superior in vitro activity of delafloxacin compared to other fluoroquinolones. Typically,
fluoroquinolones have a basic group present at C7 and are zwitterionic; however, this basic group is not
present in delafloxacin giving it a weak acid characteristic. Delafloxacin has an advantage over other
fluoroquinolones in the eradication of S. aureus with an increase in potency in acidic environments; the
bacteria has a high tolerance to low pH and survival and replication in acidic environments (skin, vagina,
urinary tract, and phagolysosomes of infected cells) given its acidic properties. [5, 6]. Delafloxacin
inhibits both bacterial topoisomerase IV and DNA gyrase (topoisomerase II) enzymes, which are required
for bacterial DNA replication, transcription, repair, and recombination. It exhibits in vitro activity against
Gram-positive and Gram-negative bacteria in a concentration-dependent bactericidal manner [4].
2.2. Pharmacodynamics
Delafloxacin has a broad spectrum of activity against Gram-negative pathogens, including P.
aeruginosa, and Gram-positive organisms, including MRSA. The activity against Gram-positive bacteria
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was demonstrated in vitro and in vivo for S. aureus (including methicillin-resistant and susceptible
strains), Staphylococcus haemolyticus, Staphylococcus lugdenensis, Streptococcus pyogenes,
Streptococcus agalactiae, Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S.
constellatus), and Enterococcus faecalis. Two global Phase III trials demonstrated susceptibility of S.
aureus to delafloxacin, which was found not to be susceptible to levofloxacin likely due to delafloxacin’s
enhanced activity at an acidic pH unlike levofloxacin that is zwitterionic [7]. The activity of delafloxacin
against Gram-negative bacteria such as Escherichia coli, K. pneumoniae, Enterobacter cloacae, and P.
aeruginosa was observed both in vitro and in clinical infections. Delafloxacin demonstrated in vitro
activity against the following organisms: Streptococcus dysgalactiae, Enterobacter aerognes,
Haemophilus parainfluenzae, Klebsiella oxytoca, Neisseria gonorrhoeae, and Proteus mirabilis; however,
it is yet to be observed in clinical infections [4, 8, 9, 10].
Delafloxacin has undergone extensive in vitro susceptibility testing against Gram-positive and
Gram-negative bacteria. Pfaller and colleagues tested delafloxacin against 573 MRSA isolates from the
US and European medical centers in the year 2014. In this study, MICs were determined using the
reference Clinical and Laboratory Standards Institute (CLSI) broth dilution method, and the
interpretation of the results were performed in accordance with the CLSI M100-S26 standard and the
European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2016 guidelines [11, 12]. The
MIC50 and MIC90 were 0.06 and 0.5 μg/mL, respectively. The Food and Drug Administration (FDA) MIC
breakpoints for susceptible S. aureus was ≤ 0.25 μg/mL. The number of S. aureus isolates totaled 1,350,
and they demonstrated MIC50 and MIC90 of ≤ 0.004 and 0.25 μg/mL, respectively. In comparison,
levofloxacin exhibited a MIC50 of 0.25 μg/mL and MIC90 of > 4 μg/mL against S. aureus. The study
included a total of 200 P. aeruginosa isolates with MIC50 of 0.25 μg/mL and MIC90 of > 4 μg/mL for
delafloxacin. The MIC50 and MIC90 of both ciprofloxacin and levofloxacin are > 4 μg/mL for P. aeruginosa.
The susceptibility of P. aeruginosa for delafloxacin was defined as an MIC of ≤ 0.5 μg/mL; therefore, P.
aeruginosa strains may be resistant to delafloxacin majority of the time, given that the MIC90 was > 4
μg/mL. Table 1 shows the interpretive criteria for susceptibility testing for delafloxacin based on FDA
breakpoints [4, 8].
2.3 Pharmacokinetics and metabolism
The absolute bioavailability of delafloxacin, following oral administration of 450-mg, is 58.8%,
and food does not alter the extent of absorption. Steady-state is achieved in approximately three days
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with a 30 to 48 L of volume of distribution of total body water. The mean half-life (t½) of delafloxacin
was 3.7 ± 0.7 hours following a single 300-mg IV infusion. Delafloxacin undergoes glucuronidation,
which is mediated by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, UGT1A3, and UGT2B15.
The plasma Cmax is achieved within 0.75 hours and 1 hour after the 450-mg oral and 300-mg IV single
dose administration, respectively. The serum Cmax achieved is 7.17 ± 2.01 μg/mL, following a single 450-
mg oral dose, and 8.94 ± 2.54 μg/mL with the administration of a single 300-mg IV dose. The total body
clearance of a single 450-mg oral dose is 20.6 ± 6.07 L/hr compared to 14.1 ± 2.81 L/hr with a single 300-
mg IV dose. Individuals with hepatic impairment did not demonstrate differences in delafloxacin
systemic exposure and clearance when compared to healthy subjects. The pharmacokinetic parameters
of oral and IV delafloxacin are expressed in Table 2 [4, 13, 14, 15].
Delafloxacin is not a known inhibitor of cytochrome P450 (CYP) enzymes at clinically relevant
concentrations. However, it mildly induced CYP3A4 at a clinically relevant concentration in human
hepatocytes [4]. Paulson and colleagues evaluated 22 individuals for an interaction between
delafloxacin and a CYP3A substrate, midazolam. They demonstrated that the steady-state dosing of
delafloxacin does not cause significant changes in the area under the curve (AUC) of midazolam [16].
Fluoroquinolones chelate with alkaline earth and transition metal cations; therefore, co-administration
of oral delafloxacin with agents containing divalent and trivalent cations (e.g. antacids, sucralfate, metal
cations, and multivitamins) should be avoided, or oral delafloxacin should be administered two hours
before or 6 hours after the cations [4].
3. CLINICAL EFFICACY
3.1 Phase II studies
O’Riordan and colleagues conducted a Phase II, randomized, double-blind, multicenter trial,
which compared delafloxacin at two distinct doses to tigecycline for complicated skin and skin-structure
infections (cSSSIs). The study included adult patients treated for cellulitis, abscess, and wound
infections, not including the presence of conditions such as diabetic foot ulcers, prosthetic device
infections, osteomyelitis, septic arthritis, necrotizing fasciitis, and severely impaired arterial blood
supply. The patients were randomized to receive delafloxacin 300 mg IV every 12 hours (n=49),
delafloxacin 450 mg IV every 12 hours (n=51), or tigecycline 50 mg IV every 12 hours following a 100-mg
loading dose (n=50) for a treatment duration of 5 to 14 days. Clinical and microbiological outcomes
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were assessed on a test-of-cure (TOC) basis between 14 and 21 days after the last dose of the study
drugs. Staphylococcus aureus was isolated in a total of 96 patients of which 71% of isolates were found
to be MRSA. Clinical cure rates at the TOC visit in the clinically evaluable population were 94.3%
(n=33/35), 92.5% (n=37/40), and 91.2% (n=31/34) in the delafloxacin 300-mg, delafloxacin 450-mg, and
tigecycline 50-mg groups, respectively. There were no statistically significant differences observed
amongst the groups with regards to cure rates between 14 and 21 days following the antibiotic
discontinuation. The authors concluded that delafloxacin demonstrated comparable effectiveness in
comparison to tigecycline in the treatment of adults with cSSSIs [17].
Kingsley and colleagues conducted another Phase II, randomized, double-blind, multicenter trial
comparing delafloxacin 300 mg IV every 12 hours (n=81) to linezolid 600 mg IV every 12 hours (n=77)
and vancomycin 15 mg/kg (n=98) in the treatment of acute bacterial skin and skin structure infections
(ABSSSIs) for a treatment duration of 5 to 14 days. The study included adult patients with
cellulitis/erysipelas, wound infection, major cutaneous abscess, or burn infection. Subjects with any of
the following were excluded from the study: infections involving prosthetic materials or foreign bodies,
infections associated with a human or animal bite, osteomyelitis, decubitus ulcers, diabetic foot ulcers,
septic arthritis, necrotizing fasciitis, burns covering ≥ 10% of body surface area, and severely impaired
arterial blood supply. Clinical cure defined as complete resolution of ABSSSIs signs and symptoms were
assessed at follow-up on day 14 ± 1. In the study, 159 of pathogens identified were S. aureus of which
66.7% were reported to be MRSA. Clinical cure rates at the time of follow-up were found to be 70.4%
(n=57/81), 64.9% (n=50/77), and 54.1% (n=53/98) in the delafloxacin, linezolid, and vancomycin groups,
respectively. The difference in clinical cure rates between delafloxacin and vancomycin was found to be
statistically significant in favor of delafloxacin (p=0.031). Delafloxacin demonstrated equal if not
improved cure rates for ABSSSIs and other infections due to MRSA [18]. (Table 4)
3.2 Phase III studies
The efficacy and safety of delafloxacin for the treatment of ABSSSI were evaluated in two phase
III studies of similar design, which led to the FDA approval of the agent. These studies were randomized,
multicenter, multinational, double-blind, double-dummy, non-inferiority, phase III trials with a total of
1,510 patients with ABSSSIs. In trial 1, delafloxacin was administered as a 300-mg IV every 12 hours, and
in trial 2, as a 300-mg IV every 12 hours for 6 doses with a mandatory switch to oral 450-mg delafloxacin
every 12 hours. The comparator in both studies was the combination of vancomycin 15 mg/kg based on
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actual body weight and aztreonam 2 grams IV every 12 hours. The ABSSSIs observed were cellulitis,
wound infections, cutaneous abscesses, and burn infections. Clinical response was defined as a 20% or
greater decrease in lesion size from the leading edge of erythema between 48 and 72 hours following
treatment initiation. Clinical response was observed in 81.3% and 80.7% of patients in the delafloxacin
and the vancomycin plus aztreonam group, respectively. Success was evaluated with a follow-up of 14 ±
1 days based on an intent-to-treat (ITT) method defined as a complete or near resolution of signs and
symptoms without the need for further antibacterial agents. The success rate of the delafloxacin group
was 84.7% and 84.1% in the vancomycin plus aztreonam group. Staphylococcus aureus (n = 643) was the
most common pathogen isolated in both groups: in the delafloxacin group, 45.1% (n=144/319) of
patients had MRSA isolated. A total of 23 P. aeruginosa isolates were observed in both groups with 11
of those in the delafloxacin group. In the delafloxacin group, there was a success rate of 84.7%
(n=122/144) and 100% (n=11/11) in the patients with MRSA and P. aeruginosa, respectively [4, 19, 20].
Given the data from the three Phase III trials, delafloxacin demonstrated non-inferiority to
current antibacterial options in the treatment of ABSSSIs caused by MDR organisms, such as P.
aeruginosa and MRSA. Table 5 summarizes the clinical outcomes from the phase III trials. Delafloxacin
is currently being studied in Phase II trial for its potential role in the treatment of serious community-
acquired bacterial pneumonia (CABP) in comparison to moxifloxacin and linezolid (ClinicalTrials.gov
identifier: NCT026795873) [22].
4. POST-MARKETING SURVEILLANCE
While the long-term extension studies and post-marketing reports will ultimately reveal more
information on the overall safety of delafloxacin, the data from the phase III clinical studies in patients
with ABSSSIs suggest that delafloxacin is generally well tolerated. However, fluoroquinolones have been
associated with potentially serious adverse effects. These serious adverse effects include tendinitis and
tendon rupture, peripheral neuropathy, exacerbation of myasthenia gravis, QTc prolongation, and
Clostridium difficile-associated diarrhea. Based on the pooled data from the two phase III ABSSSI clinical
trials, the most common adverse effects reported in patients treated with delafloxacin were nausea
(8%), diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%). The adverse
effects reported in the clinical trials did not include tendinitis and tendon rupture; however, patients
should be closely monitored for tendonitis and tendon rupture as delafloxacin is a fluoroquinolone,
which inherits the same warning [4, 19, 20, 21]. In a randomized study conducted to assess delafloxacin
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at therapeutic and supratherapeutic doses for QTc prolongation demonstrated no clinically relevant
effects on the QT/QTc interval [23]. Table 6 summarizes the safety outcomes of delafloxacin compared
to vancomycin and aztreonam in the phase III ABSSSI clinical trials.
5. REGULATORY AFFAIRS
In January 2015, Melinta Therapeutics and Eurofarma Laboratórios entered an agreement for
development and commercialization of delafloxacin in Brazil with the potential to expand into additional
Latin American countries. In June 2015, Melinta Therapeutics and Malin Plc entered an agreement for
the commercialization and distribution of delafloxacin in certain countries in the Middle East and Africa.
In March 2017, Melinta Therapeutics licensed rights of delafloxacin to the Menarini Group in 68
countries in Europe, Asia-Pacific, and the Commonwealth of Independent States [22]. In June 2017,
delafloxacin (BaxdelaTM; Melinta Therapeutics, Inc.) received approval by the US FDA for ABSSSIs in
adults caused by designated susceptible bacteria [4].
6. CONCLUSION
The fluoroquinolones as an antibiotic class are commonly utilized in numerous types of
infections. Delafloxacin is a fluoroquinolone that received recent FDA approval in June 2017 for the
treatment of ABSSSIs and is currently being investigated for its role in CABP and cUTIs. Resistance to
antibiotics, including fluoroquinolones, continues to develop. Delafloxacin is an addition to the arsenal
of currently available antibiotics in the efforts to create oral and intravenous antimicrobial regimens to
cover pathogens such as P. aeruginosa and MRSA.
7. EXPERT COMMENTARY
The major advantage delafloxacin has is its spectrum of activity that includes MDR pathogens,
such as MRSA and P. aeruginosa and its availability as an oral dosage form. Currently available
fluoroquinolones are typically not recommended for S. aureus infections since they develop resistance
rapidly. Therefore, it is imperative that we monitor the susceptibility of delafloxacin to S. aureus as it is
utilized. Among all the available antimicrobial agents, delafloxacin is the only one available as both oral
and intravenous formulations with both MRSA and P. aeruginosa activity as of now. A typical broad-
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spectrum antibiotic regimen includes an agent with MRSA coverage, such as vancomycin, in combination
with a beta-lactam that has P. aeruginosa activity with or without anaerobic coverage, such as
piperacillin/tazobactam or cefepime. Recently, the combination of vancomycin and
piperacillin/tazobactam was placed under scrutiny due to several studies reporting its increased risk of
acute kidney injury compared to the combination of vancomycin and cefepime [24, 25]. Oral
delafloxacin may be used for infections in which coverage of both MRSA and P. aeruginosa is necessary,
if delafloxacin is able to demonstrate susceptibility. It is important to keep in mind that the CLSI and
EUCAST breakpoints are imperative to determine the susceptibility of delafloxacin since the currently
available FDA breakpoints tend to be set at higher levels compared to CLSI and EUCAST, which
potentially overestimate the susceptibility.
Delafloxacin offers both oral and IV options, which allows ease of administration in both
inpatient and outpatient settings. Also, this property makes delafloxacin a favorable option for
infections that may require a prolonged course of therapy. Using oral formulation of delafloxacin may
potentially reduce duration of hospitalization as well as complications associated with IV antibiotics for
the treatment of MRSA infections. For example, delafloxacin may be useful for diabetic foot infection
and osteomyelitis cases that require long-term broad-spectrum antibiotics with an addition of
metronidazole when needed. Currently available oral agents for MRSA infections include clindamycin,
sulfamethoxazole/trimethoprim, tetracyclines, and oxazolidinones such as linezolid and tedizolid. Aside
from oxazolidinones, these oral agents have retained activity against community-associated, rather than
healthcare-associated, MRSA infections. Although oxazolidinones are considered better options for
healthcare-associated MRSA infections, they are associated with bone marrow suppression and
peripheral and optic neuropathy, particularly with long-term use. Therefore, delafloxacin has several
advantages over currently available agents.
Although these advantages might favor wide use of delafloxacin in clinical practice, collateral
damage should be monitored closely as with other fluoroquinolones. In 2016, US FDA advised limiting
the use of fluoroquinolones for certain uncomplicated infections, particularly when alternative agents
are not available [26]. Fluoroquinolones have been associated not only with tendonitis and tendon
rupture but also with central nervous system effects such as convulsions, anxiety, confusion, depression,
and insomnia, hematologic and renal toxicities, hepatotoxicity, peripheral neuropathy that may be
irreversible, and QT prolongation including torsade de pointes [27]. Although available data suggest
delafloxacin is generally well tolerated, more post-marketing surveillance data are needed. Also, since
this collateral damage is a well-known class-wide effect, patients should be closely monitored when
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delafloxacin is used. Moreover, delafloxacin may develop resistance with its use over time just like any
other antibiotics; therefore, restricting its use to providers with Infectious Diseases training or closely
monitoring its use with the aid of antimicrobial stewardship will demonstrate tremendous benefit in
preserving its effectiveness.
8. FIVE-YEAR VIEW
Currently, a trial called, DEFINE-CABP, is recruiting participants to compare delafloxacin to
moxifloxacin for the treatment of adults with CABP (NCT026795873). Previously, Flamm and colleagues
presented in vitro activity of delafloxacin against common organisms implicated in respiratory infections
such as S. pneumoniae, H. influenzae, and M. catarrhalis [9]. Given the data provide by Flamm and
colleagues, delafloxacin will likely become a popular option for the treatment of respiratory tract
infections. In near future, delafloxacin will be studied for its efficacy in the treatment of cUTI as well.
According to in vitro data, delafloxacin was active against E. coli and K. pneumoniae isolated from urine
samples of patients with suspected urinary tract infection [28].
There are investigative fluoroquinolones awaiting clinical trials to be conducted, which can lead
to US FDA approval. These new fluoroquinolones include avarofloxacin, finafloxacin, nemofloxacin, and
zabofloxacin. They exhibit increased activity and reduced likelihood of developing resistance through
higher affinity for binding to both the DNA gyrase and topoisomerase IV enzymes. Avarofloxacin
demonstrates antibacterial activity against various organisms such as S. pneumoniae, MRSA, P.
aeruginosa, N. gonorrhoeae, Enterococcus spp., E. coli, Klebsiella spp., and H. influenzae [29, 30].
Finafloxacin, like delafloxacin, is unique in that it exhibits an enhanced antibacterial activity under
conditions with a reduced pH unlike other fluoroquinolones that are zwitterionic. This property will
allow finafloxacin and delafloxacin to be effective in sites such as skin and soft tissue, vagina, respiratory
and urinary tracts, and intra-abdominal space. Also, it may potentially be used for Helicobacter pylori
infection [31, 32]. Nemofloxacin has demonstrated promising in vitro results against Gram-positive
organisms primarily against S. aureus, both methicillin-susceptible and resistant strains [33, 34, 35].
Lastly, zabofloxacin has been shown to be active against Gram-positive organisms, including S. aureus
resistant to currently available fluoroquinolones such as ciprofloxacin moxifloxacin, and gemifloxacin.
However, it has relatively reduced activity against Gram-negative organisms, particularly P. aeruginosa
and those in Enterobacteriaceae family [36].
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New fluoroquinolones in the pipeline share similar spectrum of activity with delafloxacin;
therefore, they will most likely have the same indications as delafloxacin once clinical trial data become
available. One pathogen that they may have an advantage over delafloxacin in clinical practice is N.
gonorrhoeae. After the spread of fluoroquinolone resistance among N. gonorrhoeae strains,
cephalosporins have become the basis of treatment for gonorrhea [37]. However, N. gonorrhoeae is still
considered as one of the significant pathogens for which development of new antibiotics is critical [38].
According to available data, delafloxacin has in vitro activity against N. gonorrhoeae, including those
with resistance against ciprofloxacin, azithromycin, cefixime, and ceftriaxone [10]. Nevertheless, a
phase III trial called PROCEEDING (Prove Clinical Efficacy and Effectiveness of Delafloxacin in Neisseria
gonorrhoeae) had to be terminated because of a report suggesting a single dose of delafloxacin as
monotherapy may not be enough to treat all patients [39]. Clinical trials are needed to study whether
the new fluoroquinolones will have place in gonorrhea therapy. Infectious diseases are constantly
evolving with organisms developing resistance to our currently available antimicrobials. Therefore,
development of these new antimicrobial agents is imperative to be able to treat these infections.
9. Key Issues
• Delafloxacin is a new fluoroquinolone with a chemical structure that is different from currently
available fluoroquinolones, which provides a broader spectrum of activity against MDR organisms.
• Phase II and III clinical trials demonstrated the efficacy of delafloxacin in treating ABSSSIs, including
those caused by MDR pathogens such as MRSA and P. aeruginosa.
• More studies are underway to determine the role of delafloxacin in the treatment of CABP and
potentially cUTI.
• Delafloxacin is generally well tolerated and may potentially have an improved side effect profile to
currently available fluoroquinolones with respect to QTc prolongation and tendinitis and tendon
rupture.
• Delafloxacin should be used judiciously to preserve its effectiveness and prevent collateral damage.
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Funding
The manuscript was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony,
grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Company disclosures
Melinta Therapeutics provided a scientific accuracy review at the request of the journal editor.
Acknowledgements
No other authors except for the ones listed on the first page of this article helped to write or revise the
manuscript. All authors contributed equally in the writing and revising of this manuscript.
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Reference annotations
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FIGURE Figure 1: Chemical structure of delafloxacin [4] Figure 1: Chemical structure of delafloxacin [4]
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TABLES Table 1: Susceptibility test interpretive criteria for delafloxacin [4] Table 2: Pharmacokinetic properties of oral and intravenous delafloxacin [4] Table 3: Dosage adjustments for patients with renal impairment [4] Table 4: Phase II clinical response for skin and skin-structure infections [17, 18] Table 5: Phase III clinical response for acute bacterial skin and skin structure infections [4, 19, 20, 21] Table 6: Summary of safety outcomes in clinical trials [4, 19, 20] Table 1: Susceptibility test interpretive criteria for delafloxacin [4] Minimum Inhibitory
Concentrations (μg/mL) Disk Diffusion
(Zone Diameter in mm) Pathogen S I R S I R
Staphylococcus aureus ≤ 0.25 0.5 ≥ 1 ≥ 23 20-22 ≤ 19 Staphylococcus haemolyticus ≤ 0.25 0.5 ≥ 1 ≥ 24 21-23 ≤ 20 Streptococcus pyogenes ≤ 0.06 - - ≥ 20 - - Streptococcus agalactiae ≤ 0.06 0.12 ≥ 0.25 - - - Streptococcus anginosus Group ≤ 0.06 - - ≥ 25 - - Enterococcus faecalis ≤ 0.12 0.25 ≥ 0.5 ≥ 21 19-20 ≤ 18 Enterobacteriaceae ≤ 0.25 0.5 ≥ 1 ≥ 22 19-21 ≤ 18 Pseudomonas aeruginosa ≤ 0.5 1 ≥ 2 ≥ 23 20-22 ≤ 19 S = susceptible; I = intermediate; R = resistant Table 2: Pharmacokinetic properties of oral and intravenous delafloxacin [4]
Parameters
Oral Tablet Intravenous Infusion Single Dose
450-mg Steady State
450-mg every 12 hours Single Dose
300-mg Steady State
300-mg every 12 hours Tmax (hours) 0.75 (0.5-4) 1 (0.5-6) 1 (1-1.2) 1 (1-1) Cmax (μg/mL) 7.17 ± 2.01 7.45 ± 3.16 8.94 ± 2.54 9.29 ± 1.83 AUC (μg·h/mL) 22.7 ± 6.21 30.8 ± 11.4 21.8 ± 4.54 23.4 ± 6.9 Clearance (L/h) 20.6 ± 6.07 16.8 ± 6.54 14.1 ± 2.81 13.8 ± 3.96 Cmax = maximum concentration; Tmax = time to reach Cmax; AUC = area under the concentration-time curve Table 3: Dosage adjustments for patients with renal impairment [4] eGFR (mL/min/1.73 m2) Recommended Dosage Regimen
Oral Tablets Intravenous 1 Hour Infusion 30-89 450 mg every 12 hours 300 mg every 12 hours 15-29 450 mg every 12 hours 200 mg every 12 hours < 15 OR HD Not recommended eGFR (mL/min/ 1.73 m2) = 175 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 if female) x (1.212 if African American)
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Table 4: Clinical outcomes of delafloxacin for skin and skin-structure infections in phase II trials [17, 18] Trial Antibiotic
O’Riordan, et al Delafloxacin 300 mg Delafloxacin 450 mg Tigecycline Cure rate 33/35 (94.3%) 37/40 (92.5%) 31/34 (91.2%) Kingsley J, et al. Delafloxacin 300 mg Linezolid 600 mg Vancomycin 15 mg/kg Cure rate 57/81 (70.4%) 50/77 (64.9%) 53/98 (54.1%)* *p < 0.05 versus delafloxacin Table 5: Clinical outcomes of delafloxacin for acute bacterial skin and skin structure infections in phase III trials [4, 19, 20, 21]
Trial Delafloxacin Vancomycin 15 mg/kg + Aztreonam
Treatment Difference(2-sided 95% CI)
Trial 1 300-mg Intravenous
Total N 331 329 Clinical response, n (%) 259 (78.2%) 266 (80.9%) -2.6 (-8.8 to 3.6) Success ITT, n (%) 270 (81.6%) 274 (83.3%) -1.7 (-7.6 to 4.1) Success CE, n/N (%) 232/240 (96.7%) 238/244 (97.5%) -0.9 (-4.3 to 2.4)
Trial 2 300-mg Intravenous And 450-mg
Oral
Total N 423 427 Clinical response, n (%) 354 (83.7%) 344 (80.6%) 3.1 (-2 to 8.3) Success ITT, n (%) 369 (87.2%) 362 (84.8%) 2.5 (-2.2 to 7.2) Success CE, n/N (%) 339/353 (96%) 319/329 (97%) -0.9 (-3.9 to 2)
Trial 3 300-mg Intravenous
Total N 331 329 Objective response, n (%) 259 (787.2%) 266 (80.9) -2.6 (-8.78 to 3.57) Investigator assessed cure, n (%) 172 (52%) 166 (50.5%) 1.5 (-6.11 to 9.11)CI = confidence interval; ITT = intent to treat and includes all randomized patients; CE = clinically evaluable consisted of all ITT patients who had a diagnosis of ABSSSI, received at least 80% of expected doses of study drug, did not have any protocol deviations that would affect the assessment of efficacy and had investigator assessment at the follow-up visit. Table 6: Summary of safety outcomes in phase III clinical trials [4, 19, 20]
Adverse Reactions Delafloxacin N = 741 (%)
Vancomycin/Aztreonam N = 751 (%)
Nausea 8% 6% Diarrhea 8% 3% Headache 3% 6% Transaminase elevations 3% 4% Vomiting 2% 2%
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