Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=ierz20

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.

Submit your article to this journal

View related articles

View Crossmark data

Accep

ted M

anus

cript

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: Eric.Ocheretyaner@liu.edu 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:

Accep

ted M

anus

cript

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: Eric.Ocheretyaner@liu.edu

Accep

ted M

anus

cript

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

Accep

ted M

anus

cript

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

Accep

ted M

anus

cript

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

Accep

ted M

anus

cript

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

Accep

ted M

anus

cript

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

Accep

ted M

anus

cript

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

Accep

ted M

anus

cript

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

Accep

ted M

anus

cript

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-

Accep

ted M

anus

cript

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

Accep

ted M

anus

cript

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].

Accep

ted M

anus

cript

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.

Accep

ted M

anus

cript

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.

Accep

ted M

anus

cript

REFERENCES

Reference annotations

* Of interest

** Of considerable interest

1. Van Bambeke F. Delafloxacin, 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.

2. Centers for Disease Control and Prevention (CDC). About Antimicrobial Resistance.

https://www.cdc.gov/drugresistance/about.html. Last updated April 6, 2017.

3. Kocsis B, Domokos J, Szabo D. Chemical structure and pharmacokinetics of novel quinolone agents

represented by avarofloxacin, delafloxacin, finafloxacin, zabofloxacin and nemonoxacin. Ann Clin

Microbiol Antimicrob 2016;15:34

*A comprehensive review comparing the chemical structure, pharmacokinetics and activity of

current and studied fluoroquinolones.

4. Baxdela® (delafloxacin) [package insert] Lincolnshire, IL: Melinta Therapeutics, Inc; 2017.

5. Candel FJ, Peñuelas M. Delafloxacin: design, development and potential place in therapy. Drug

Design, Development and Therapy 2017;11:881-91.

6. Lemaire S, Tulkens PM, Van Bambeke F. Contrasting Effects of Acidic pH on the Extracellular and

Intracellular Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and Delafloxacin

against Staphylococcus aureus. Antimicrob Agents Chemother 2011; 55(2):649-58.

*A comprehensive review of the effects of pH on the activity exerted by fluoroquinolones on

Gram-positive pathogens.

7. 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;61(9):e00772-17.

8. Pfaller MA, Sader HS, Rhomberg PR, et al. In Vitro Activity of Delafloxacin against Contemporary

Bacterial Pathogens from the United States and Europe, 2014. Antimicrob Agents Chemother

2017;61(4):e02609-16

Accep

ted M

anus

cript

**In vitro activity of delafloxacin and comparator antimicrobials against bacterial isolates

collected in the United States and Europe.

9. Flamm RK, Rhomberg PR, Huband MD, et al. In Vitro Activity of Delafloxacin Tested against Isolates

of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrob

Agents Chemother 2016;60(10):6381-85.

10. Soge OO, Salipante SJ, No D, et al. In Vitro Activity of Delafloxacin against Clinical Neisseria

gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance. Antimicrob Agents

Chemother 2016;60(5):3106-11.

11. Clinical and Laboratory Standards Institute. 2016. M100-26. Performance standards for antimicrobial

susceptibility testing: 26th informational supplement. Clinical and Laboratory Standards Institute,

Wayne, PA.

12. EUCAST. 2016. Breakpoint tables for interpretation of MICs and zone diameters, version 6.0,

January. http://www/eucast.org/clinical_breakpoints/.

13. Hoover R, Marbury TC, Preston RA, et al. Clinical Pharmacology of Delafloxacin in Patients With

Hepatic Impairment. J Clin Pharmacol 2017;57(3):328-35.

14. Hoover R, Hunt T, Benedict M, et al. Safety, Tolerability, and Pharmacokinetic Properties of

Intravenous Delafloxacin After Single and Multiple Doses in Healthy Volunteers. Clin Ther

2016;38:53-65.

15. 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;38:39-52.

16. Paulson SK, Wood-Horrall RN, Hoover R, et al. The Pharmacokinetics of the CYP3A Substrate

Midazolam After Steady-state Dosing of Delafloxacin. Clin Ther 2017;39(6):1182-90.

17. O’Riordan W, Mehra P, Manos P, et al. A randomized phase 2 study comparing two doses of

delafloxacin with tigecycline in adults with complicated skin and skin-structure infections. Int J

Infect Dis 2015;30:67-73.

18. 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 ad skin structure infections

treated with delafloxacin, linezolid or vancomycin. J Antimicrob Chemother 2016;71:821-829.

19. Cammarata S, Gardovskis J, Farley B, et al. Results of A Global Phase 3 Study of Delafloxacin (DLX)

Compared to Vancomycin with Aztreonam (VAN) in Acute Bacterial Skin and Skin Structure

Infections (ABSSSI). Abstract presented at: ID Week Meeting; October 7-11, 2015; San Diego, CA.

Accep

ted M

anus

cript

20. O’Riordan W, McManus A, Teras J, et al. A Global Phase 3 Study of Delafloxacin (DLX) Compared to

Vancomycin/ Aztreonam (VAN/AZ) in Patients with Acute Bacterial Skin and Skin Structure Infections

(ABSSSI). Abstract presented at: ID Week Meeting; October 26-30, 2016; New Orleans, LA.

**A phase 3, multicenter, randomized, multinational, double-dummy, non-inferiority study

supporting the safety and efficacy of delafloxacin in ABSSSIs.

21. 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.

** A phase 3, multicenter, randomized, multinational, double-dummy, non-inferiority study

supporting the safety and efficacy of delafloxacin in ABSSSIs.

22. Melinta Therapeutics, Inc. The Antibiotics Company. Baxdela (Delafloxacin): United States.

http://melinta.com/pipeline/baxdela/. Accessed December 28. 2017.

23. Litwin JS, Benedict MS, Thorn MD, et al. A Thorough QT Study To Evaluate the Effects of Therapeutic

and Subtherapeutic Doses of Delafloxacin on Cardiac Reploarization. Antimicrob Agents and

Chemother 2015;59(6):3469-73.

24. Jeon N, Staley B, Klinker KP, et al. Acute kidney injury risk associated with piperacillin/tazobactam

compared with cefepime during vancomycin therapy in hospitalized patients: a cohort study

stratified by baseline kidney function. Int J Antimicrob Agents 2017;50(1):63-7.

25. Navalkele B, Pogue JM, Karino S, et al. Risk of Acute Kidney Injury in Patients on Concomitant

Vancomycin and Piperacillin-Tazobactam Compared to Those on Vancomycin and Cefepime. Clin

Infect Dis 2017;64(2):116-23.

26. U.S. Food and Drug Administration (FDA). 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. Last

updated October 12, 2017.

27. Levaquin® (levofloxacin) [package insert] Lake Forest, IL: Hospira, Inc; 2008.

28. Melinta Therapeutics. Melinta Therapeutics and Hartford Hospital Demonstrate Delafloxacin’s

Potent in-vitro Activity Against Complicated Urinary Tract Infection Pathogens.

http://melinta.com/melinta-therapeutics-and-hartford-hospital-demonstrate-delafloxacins-potent-

in-vitro-activity-against-complicated-urinary-tract-infection-pathogens/. Accessed January 1, 2018.

29. Morrow BJ, He W, Amsler KM, et al. In vitro antibacterial activities of JNJ-Q2, a new broad-spectrum

fluoroquinolone. Antimicrob Agents Chemother 2010;54(5):1955-64.

Accep

ted M

anus

cript

30. Biedenbach DJ, Turner LL, Jones RN, et al. Activity of JNJ-Q2, a novel fluoroquinolone, tested against

Neisseria gonorrhoeae, including ciprofloxacin-resistant strains. Diagn Microbol Infect Dis

2012;74(2):204-6.

31. Patel H, Anderson A, Vente A, et al. Human pharmacokinetics and safety profile of finafloxacin a

new fluoroquinolone antibiotic in healthy volunteers. Antimicrob Agents Chemother 2011;55:4386-

93.

32. Buissonniere A, Bergey B, Megraud F, et al. In: Antimicrobial activity of finafloxacin (FIN) against

Helicobacter pylori in vitro and in vivo. Proceedings of the 48th interscience conference of

antimicrobial agents and chemotherapy, Washington, USA, October 25-28, 2008.

33. Adam HJ, Laing NM, King CR, et al. In vitro activity of nemofloxacin a novel nonfluorinated

quinolone against 2440 clinical isolates. Antimicrob Agents Chemother 2009;53:4915-20.

34. Barry AL, Fucgs PC, Brown SD. In vitro activities of three non-fluorinated quinolones against

representative bacterial isolates. J Antimicrob Chemother 2009;64:1923-7.

35. Chen YH, Liu CY, Lu JJ, et al. In vitro activity of nemonoxacin (TG-873870) a novel non-fluorinated

quinolone against clinical isolates of Staphylococcus aureus and enterococci and Streptococcus

pneumoniae with various resistance phenotypes in Taiwan. J Antimicrob Chemother 2009;64:1226-

9.

36. Park HS, Kim HJ, Seol MJ, et al. In Vitro and In Vivo Antibacterial Activities of DW-224a, a New

Fluoronaphthyridone. Antimicrob Agents Chemother 2006;50(6):2261-4.

37. Centers for Disease Control and Prevention (CDC). Antibiotic-Resistant Gonorrhea.

https://www.cdc.gov/std/gonorrhea/arg/default.htm. Last updated December 6, 2017.

38. Tacconelli E, Carrara E, Savoldi A, et al. Discovery, research, and development of new antibiotics:

the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2017; S1473-

3099(17)30753-3. doi: 10.1016/S1473-3099(17)30753-3.

39. Melinta Therapeutics. Melinta Therapeutics Ceases Phase 3 PROCEEDING Study.

http://melinta.com/melinta-therapeutics-ceases-phase-3-proceeding-study/. Accessed January 1,

2018.

Accep

ted M

anus

cript

FIGURE Figure 1: Chemical structure of delafloxacin [4] Figure 1: Chemical structure of delafloxacin [4]

Accep

ted M

anus

cript

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)

Accep

ted M

anus

cript

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%

本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具