Delafloxacin: A New Anti-MRSA Fluoroquinolone

Louis D. Saravolatz, MD, MACP, FIDSA and Gary E. Stein, Pharm D

St John Hospital and Medical Center

Grosse Pointe Woods, Michigan

Michigan State University School of Medicine

East Lansing, Michigan

Corresponding Author:
Louis D Saravolatz, MD, MACP, FIDSA
19251 Mack Ave.
Grosse Pointe Woods, Michigan, 48236
Phone: 313-343-3362
Fax: 313-343-7784
E mail: louis.saravolatz@stjohn.org

Summary: Delafloxacin is new anti MRSA fluoroquinolone available in both oral and

parenteral formulations that has been approved for acute bacterial skin and skin

structure infections. Delafloxacin has a favorable adverse event profile but its clinical

utility will require further study.

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of
America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

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 Abstract:

Delafloxacin (ABT 492) is a new fluoroquinolone available in both oral and parenteral

formulations. It has recently been approved by the FDA for the management of acute

bacterial skin and skin structure infections. When compared to combination therapy of

vancomycin and aztreonam, delafloxacin was not inferior and had a favorable adverse

event profile. Furthermore, its anti-MRSA activity and favorable clinical response in

MRSA infections distinguishes it from other fluoroquinolones. This review focuses on

the mode of action, antimicrobial activity, pharmacokinetics and pharmacodynamics,

clinical indications, and safety profile of this drug. Considerations for formulary addition

and its place in therapy are also discussed.

Key words: delafloxacin, fluoroquinolones, MRSA

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 Structural modifications have resulted in the production of numerous quinolones since

the introduction of the first quinolone, nalidixic acid, in 1962. Modifications have led to

compounds to improve potency, the spectrum of antibacterial activity, and to improve

the pharmacokinetic and pharmacodynamic properties of quinolones. In 2017, the

United States Food and Drug Administration (FDA) approved the newest

fluoroquinolone, delafloxacin, previously referred to as ABT 492. This agent is available

in parenteral and oral forms. Delafloxacin has the advantage of improved in vitro

coverage against Gram-positive pathogens specifically methicillin-resistant

Staphylococcus aureus (MRSA). The mode of action, spectrum of activity,

pharmacokinetics and pharmacodynamics, clinical indications, and adverse events of

this drug are reviewed here. In addition, comments on formulary considerations are

included.

Chemistry and Mode of Action

The chemistry of delafloxacin provides this fluoroquinolone with several

antimicrobial advantages compared to older agents (Figure 1). The difluoro-2-pyridinyl

structure at the R1 position enhances the potency of this agent especially against gram-

positive organisms (1). The R7 substitution (3-hydroxy-1-azetidinyl) renders this

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 molecule to be a weak acid (pKa 5.4). Thus, delafloxacin is primarily uncharged in

inflammatory (acidic) environments which facilitates transmembrane passage into the

bacterial cell. Inside the cell, at neutral pH, this fluoroquinolone will be in its ionic form

and retained in the bacteria (2). This results in an increase in potency compared to

previous fluoroquinolones. The chlorine atom at the C-8 position of delafloxacin

stabilizes this compound, confers excellent potency and may reduce the development of

resistance. Furthermore, the contribution of this atom along with the R7 substitution

enhances the activity of delafloxacin against anaerobic bacteria.

The fluoroquinolones target bacterial topoisomerase enzymes which mediate

DNA-strand breakage and reunion. Topoisomerase II (DNA gyrase) is more susceptible

to fluoroquinolone inhibition in Gram-negative bacteria whereas topoisomerase IV is

more susceptible to inhibition in Gram-positive bacteria. Treatment with these drugs

leads to double-strand DNA breaks and cell death. Delafloxacin is a broad-spectrum

agent and targets both DNA gyrase and topoisomerase IV (3). The substitutions at the

C-7 and C-8 positions of delafloxacin influences its potency and spectrum of activity.

Moreover, this fluoroquinolone structure appears stable against bacterial modifications

and resistance requires the accumulation of several mutations that affect both

topoisomerase targets (4).

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 Antimicrobial Activity

Delafloxacin is a fluoroquinolone with in vitro activity against a broad range of Gram-

positive and Gram-negative bacteria, anaerobes, Neisseria gonorrhoeae, atypical

respiratory pathogens including Legionella sp, Chlamydia pneumoniae, and

mycoplasma (table 1). (3,5-10). The susceptibility breakpoint for delafloxacin against

Staphylococcus aureus is < 0.25 µg per ml per Clinical Laboratory Standard Institute

(CLSI). From table 1, 98.5% of 591 MSSA and 87.6% of 509 contemporary United

States MRSA isolates were susceptible to delafloxacin (5). The intermediate

breakpoint MIC is 0.5 µg per mL and the resistance breakpoint is > 1.0 µg per mL

There is no data published on the activity of delafloxacin against more resistant strains

including those resistant to agents that include linezolid, daptomycin, and vancomycin,

both intermediate and resistant strains. Delafloxacin’s susceptibility breakpoint against

Enterococcus faecalis requires a MIC < 0.12 µg per ml and 73% met this criterion but

only 4.6% of the E faecium were susceptible. The susceptible breakpoint for

delafloxacin against S hemolyticus and enterobacteriaceae is <0.25 µg per mL with

intermediate and resistance breakpoints being 0.5 and >1.0 µg per mL, respectively.

For Pseudomonas aeruginosa the susceptible, intermediate, resistant breakpoints are

<0.5, 1, >2 µg per ml, respectively. Using CLSI breakpoints only 54% of Pseudomonas

aeruginosa were susceptible. Thus, like levofloxacin and ciprofloxacin, resistance

already exists among many strains of Pseudomonas aeruginosa as well as other strains

of enterobacteriaceae including Serratia, Citrobacter, Proteus mirabilis, Klebsiella, and

Escherichia coli (table 1).

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 Delafloxacin demonstrated good activity against sexually transmitted disease pathogens

including Neisseria gonorrhea, and Ureaplasma species (table 1) (7,9). It also

demonstrated good activity against respiratory pathogens including Mycoplasma

pneumoniae, Chlamydia pneumoniae, but no data on intracellular killing for Legionella

pneumophila has been published.

Harnett demonstrated that delafloxacin had an MIC of 0.03 µg per ml against 9 strains

of Clostridium difficile (10). In contrast to ciprofloxacin and levofloxacin, delafloxacin

exhibited good activity against Clostridium perfringens, Bacteroides fragilis, Prevotella

sp, Peptostreptococcus, and Bacteroides thetaiotamicron.

In in vivo biofilm models with Gram-positive organisms, delafloxacin demonstrated

increased penetration within biofilms which was as effective as daptomycin and

vancomycin in the same model in reducing viability of the bacterial strains tested (11).

Delafloxacin also demonstrated higher concentrations within the biofilms and high

potency at the local acidic pH of the model. This model suggests that delafloxacin

should be considered in further clinical trials evaluating infections related to biofilm

formation.

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 Pharmacokinetics and Pharmacodynamics
Delafloxacin can be administered by oral tablet or intravenous (IV) infusion. A

higher oral dose (450mg) is required to achieve a similar concentration-time profile as

an IV dose (300mg). The oral bioavailability (59%) of delafloxacin is not altered by food

but can be significantly reduced if taken concomitantly with drugs or products that

contain multi-valent metal cations such as Al, Mg, Fe or Zn. Maximum concentrations

are achieved in about 1 hour and range from 7.5 (oral) to 9.3 (IV) mg/L at steady-state

(12). No accumulation occurs following multiple dosages.

Delafloxacin has a large volume of distribution (~0.4 L/kg) which approximates

total body water. In plasma, it is primarily bound to albumin (84%). Thus, the free-drug

area under the concentration-time curve over 24 hours is diminished (ƒAUC24 ~

8mg∙h/L). Much of parenteral delafloxacin is excreted in the urine as free drug (45%)

and glucuronide metabolites. A reduced IV dosage (200mg) is recommended to avoid

the accumulation of cyclodextrin in renal tissues of patients with an estimated

glomerular filtration rate < 30 mL/min (13). This dosage adjustment still provides

therapeutic serum concentrations of delafloxacin. No dosage reduction is

recommended in these patients when delafloxacin is administered orally. There are no

recommendations for intravenous or oral dosing when the estimated glomerular filtration

rate is <15 mL per minute. There is minimal (~1%) oxidative metabolism of this

fluoroquinolone and no clinically relevant inhibition of cytochrome P450 enzymes (14).

Dosage adjustment is not required in patients with hepatic impairment (15).

The fluoroquinolones exhibit concentration-dependent antibacterial effects and the

ƒAUC24/MIC ratio is the main pharmacodynamic (PD) determinant of efficacy. In murine

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 lung infection models, the median ƒAUC24/MIC ratios for delafloxacin to produce

bacterial stasis were ≤ 40 for strains of S. pneumoniae, S. aureus and K. pneumoniae

(16,17). Moreover, median ratios of < 15 for bacterial stasis were observed for strains of

E. coli and P. aeruginosa in a murine thigh infection model. The results from these

studies suggest that PD efficacy can be achieved with delafloxacin at considerably

lower ƒAUC24/MIC ratios than older fluoroquinolones (18). Delafloxacin has

also demonstrated potent activity against intracellular S.aureus(19). Moreover,

delafloxacin exhibited comparable antibiotic activity to daptomycin in S. aureus biofilms

(20).

Although the results from in vitro and animal models are insufficient for definitive

conclusions concerning the PD index necessary for human infections, these findings

have potential relevance for clinical dose selection as well as determining susceptibility

breakpoints. The ƒAUC24 obtained from both oral and IV dosing regimens of

delafloxacin appears adequate to treat susceptible Gram-positive and Gram-negative

bacterial pathogens. Additional clinical PD studies will be necessary to determine

whether the current susceptibility breakpoints for delafloxacin are appropriate and

support good clinical efficacy.

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 Clinical Indications

Delafloxacin has been approved by the FDA for the treatment of complicated acute

bacterial skin and skin structure infections (ABSSSI). The largest trial leading to this

approval was performed by O’Riordan (21). This study was a phase 3, multicenter,

stratified, randomized, double-blind, active-controlled trial. Patients were randomized

1:1 and stratified by infection category and baseline BMI. The study was double-

blinded, however, a nonblinded pharmacist was responsible for preparation of the study

drug and ensuring infusion bags were indistinguishable. The objective of the study was

to assess the clinical efficacy of delafloxacin (300 mg IV, twice a day ×6 doses, and a

switch to 450 mg by mouth twice a day for total of 10-28 doses) compared to

vancomycin (15 mg/kilogram) and aztreonam (2g BID for a total of 10-28 doses) in

patients who had ABSSSI at 48-72 hours after initiation of treatment. The primary

endpoint was investigator assessed response based on resolution of signs and

symptoms at 48-72 hours. Response on days 14 and 21-28 were secondary endpoints.

Patients had to be 18 years of age and had to have had a diagnosis of ABSSSI

classified as cellulitis, wound infection, major cutaneous abscess, or burn infection with

greater than or equal to 75 cm² of erythema and two signs of systemic infection. They

had to have been candidates for intravenous therapy. Patients were excluded if they

had a history of hypersensitivity or allergic reactions to quinolones, beta-lactams, or

vancomycin. They were also excluded if they had received systemic antibiotic therapy

in the 14 days prior to enrollment unless one of the following was documented: clinical

progression of ABSSSI or only one dose of a single potentially effective antibiotic had

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 been administered. They were also excluded if their body weight was greater than 140

kg.

The 850 patients randomized into the study were similar in terms of age, gender, race

and ethnicity, mean BMI, and presence of diabetes. Among the 850 patients enrolled,

552 had bacterial pathogens known to cause ABSSSI. All the enrolled patients

receiving at least one dose of the study drug were evaluated for safety.

The primary outcome for this study was an objective response at 48-72 hours following

treatment initiation defined as a greater than or equal to 20% reduction in erythema.

The objective response was 83.7% for delafloxacin and 80.6% for the vancomycin

aztreonam arm. The difference in responder rates was 3.1% (95% CI, -2.0%, 8.3%),

demonstrating that delafloxacin was non-inferior compared to the vancomycin plus

aztreonam group in the intent to treat (ITT) analysis. The overall pathogen eradication

rates were similar with delafloxacin and vancomycin plus aztreonam of, 97.8% and

97.6% respectively, with a difference of 0.2% (95% CI, -2.9%, 3.5%).

The EMA defined primary efficacy measure was the investigator assessed response of

signs or symptoms of infection at the follow-up 14 day visit in the ITT population. Cure

was defined as complete resolution of symptoms and was 57.7% and 59.7%

respectively for delafloxacin versus vancomycin and aztreonam arm at the 14-day visit.
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 A secondary outcome was the evaluation of the microbiologic response for MRSA

infections. It was similar in the two study groups at 96 and 97% for the delafloxacin and

vancomycin/aztreonam arms, respectively. No emergence of resistance occurred

among S. aureus.

A second phase 3 study of 666 patients demonstrated a similar response of delafloxacin

compared to vancomycin plus aztreonam in the treatment of ABSSSI (22). The study

enrolled 660 patients. The objective response of 48-72 hours was 78.2% in the

delafloxacin arm and 80.9% (mean treatment difference, -2.6%; 95% CI, -8.78% to

3.57%). MRSA eradication was 100% and 98.5% in the delafloxacin group and the

vancomycin/aztreonam group, respectively. Although the study concluded that

delafloxacin offered a potential treatment option without the need for combination

therapy, the study was limited by being in a younger population with a mean age < 46.3

year and a lower number of diabetics (9.1% in the delafloxacin arm and 8.2% in the

vancomycin plus aztreonam arm). A follow-up in vitro evaluation was published that

indicated that all isolates from the above two trials had MIC 90s for Staphylococcus

aureus of 0.25 mcg/mL and S aureus was eradicated or presumed eradicated in 98.4%

of delafloxacin treated patients. Furthermore, there was no emergence of delafloxacin

resistance during therapy in these studies and delafloxacin demonstrated similar

eradication rates for levofloxacin non- susceptible and susceptible S. aureus. (23)

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 At the time of the publication of this paper the FDA has only approved delafloxacin for

the treatment of acute bacterial skin and skin structure infections. Although the in vitro

activity of delafloxacin would suggest that it has utility for other sites of infections such

as the respiratory tract including atypical pathogens, genitourinary tract infections and

intra-abdominal infections, additional clinical trials will need to be published to support

other indications.

Adverse Events:

The overall rate of serious adverse events was comparable in the two treatment groups

and there were two deaths both occurring in the vancomycin aztreonam group during

the O’Riordan study (21). Among the 842 patients who received at least one dose of

the drug, adverse events were reported in 43.6% of delafloxacin arm and 39.3% of the

vancomycin plus aztreonam arm. Treatment emergent adverse events were similar

between the two treatment arms. However, delafloxacin had lower rates of

discontinuation than the vancomycin plus aztreonam arm, 1.2% versus 2.4%,

respectively. The most common events were gastrointestinal, with nausea 7.7%,

diarrhea 7.7%, and vomiting 2.4%, occurring in the delafloxacin arm. These were higher

than the arm with vancomycin and aztreonam therapy. There was one case of
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 Clostridium difficile in the delafloxacin arm and none in the vancomycin aztreonam arm.

Other associated adverse events that occurred in more than 2% of patients included

headache, infusion site extravasation, and fever. There were no cases of tendinitis,

tendon rupture, or myopathy and one case of paresthesias in each treatment arm.

There were two deaths that occurred vancomycin plus aztreonam group and none in the

delafloxacin treated group.

The adverse events in the Pullman study were very similar to the O’Riordan study

however again noting that diarrhea occurred in 7.7% of the delafloxacin group versus

only 3.3% in the vancomycin plus aztreonam group. There were no cases of C. difficile

reported. Although there were some cases of dysglycemia, there were a few events

and they occurred across both cohorts. Although phototoxicity was not mentioned in

the adverse event summaries of the clinical trials, one still needs to be cautious as the

drug was administered largely in the hospital setting and the phototoxic potential may

not be realized until the drug has more widespread use in the ambulatory setting.

QT prolongation and Torsades has been an adverse event of concern for

fluoroquinolones. Litwin et al performed a rigorous QT study to evaluate the effects of

therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization (24).

This study involved a single dose of delafloxacin at therapeutic dosing of 300 mg

intravenously and a supratherapeutic dose of 900 mg as a single dose given

intravenously compared to moxifloxacin at 400 mg by mouth, also as a single dose.

There was no clinically meaningful increase in QTcF interval in either of the two

delafloxacin doses. In fact, QTcF for delafloxacin was reduced in subjects compared to

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 their baseline. This study is limited in that it was conducted in healthy relatively young

(age 18-45 years) male and female subjects with no comorbidities or concomitant

medications.

Formulary Considerations

The fluoroquinolone of choice is often predicated by the type of infection and its

microbiology. Delafloxacin has demonstrated broad-spectrum activity including

nosocomial and atypical pathogens. This fluoroquinolone further distinguishes itself

from older agents due to its activity against MRSA. Two clinical trials have found

delafloxacin to be non-inferior to a two-drug regimen of antibiotics in the treatment of

complicated acute bacterial skin/skin structure infections including patients with MRSA

(20,21). Due to its enhanced potency in acidic environments, delafloxacin also has the

potential to be highly effective in the treatment of pneumonia and urinary tract

infections, but future trials are needed to support these indications (25). Furthermore,

the potent antimicrobial activity of delafloxacin against anaerobic pathogens may allow

for single-drug treatment of polymicrobial infections, such as decubitus ulcers and intra-

abdominal infections. Additional clinical trials are anticipated and will help determine the

clinical role for delafloxacin’s use beyond the current FDA approved (ABSSSI)

indication.

One of the major concerns with high-level use of a broad-spectrum

fluoroquinolone, such as delafloxacin, is the selection and spread of quinolone-resistant

microorganisms. Fluoroquinolone resistance not only appears in topoisomerase targets

but can also include transferable mechanisms that involve target protection, structure

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 modification, and efflux systems (26). In vitro studies have demonstrated a low potential

for selection of resistance to delafloxacin in S. aureus albeit mutants were selected at

low frequencies from quinolone-resistant isolates (4). Further clinical investigations will

be necessary to determine whether delafloxacin exhibits a low probability for selection

of resistant mutants in S. aureus as well as Gram-negative bacterial pathogens such as

P. aeruginosa.

Delafloxacin has been well tolerated in initial clinical trials to date. It is not known

whether fluoroquinolone-associated untoward events such as tendinitis, peripheral

neuropathy, dysglycemia, and central nervous system effects will be a concern with

more extensive delafloxacin use. These serious adverse events have tempered the use

of all fluoroquinolones for common bacterial infections and they are now recommended

only for patients who lack other treatment options. Fluoroquinolone treatment has also

been associated with increased rates of C. difficile associated diarrhea (CDAD). Due to

its potent in vitro activity against C. difficile isolates, delafloxacin may not generate an

increased risk of this infection but post marketing surveillance will be needed to

ascertain an accurate incidence of CDAD. Delafloxacin may also prove safer than older

fluoroquinolones due to its lack of both metabolic drug-drug interactions and QTc-

prolongation (24). There are no studies of delafloxacin in pregnant women or those who

were breast-feeding.

Finally, the cost of a new antimicrobial agents must also be a consideration in

drug selection. The acquisition cost of delafloxacin could be several fold higher than

older fluoroquinolones (27) and also higher than other generic agents such as linezolid.

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 Cost-effective studies will need to be performed and critically analyzed to aid in

determining where delafloxacin should be used. These may include deep-seated tissue

abscesses due to MRSA, patients with complicated polymicrobial infections, or when

parenteral-to-oral treatment conversion is warranted. In a field where we already have

multiple oral and parenteral anti-MRSA agents including sulfamethoxazole/trimethoprim,

doxycycline, linezolid, clindamycin, vancomycin, daptomycin, ceftaroline, and

telavancin, delafloxacin’s role as a new anti-MRSA agent with both an oral and

intravenous formulation may have a role that price alone should not dictate but will need

to be defined by future studies.

Financial Disclosures

Louis D. Saravolatz and Gary E Stein both report payments from Melinta outside the
submitted work.

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Figure 1: Delafloxacin Structure

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 Table 1 Comparative in vitro % Susceptibility and MIC 90’s of Delafloxacin (3, 5-10)

Organism (number of isolates tested) % Susceptible MIC90

MSSA (591) 98.50% 0.008
MRSA (509) 87.60% 0.5
Coagulase- negative Staphylococcus 86.00%
Methicillin susceptible (75) ---- 0.06
Methicillin resistant (125) ---- 0.5
Enterococcus faecalis (300) 73.00% 1
Enterococcus faecium (295) 4.60% >4
Viridans group streptococci (294) 95.40% 0.03
H. Influenzae (200) ---- 0.004
M. catarrhalis (100) ---- 0.008
Streptococcus pneumoniae (300) 100% 0.15
Streptococcus pyogenes (433) 100% 0.015
Streptococcus agalactiae (225) 98% 0.15
M. pneumoniae (101) ---- 0.5
C. pneumoniae (13) ---- 0.125
L. pneumophila (14) ---- 0.12
Streptococcus dysgalactiae (132) 100% 0.015
Listeria monocytogenes (15) ---- 0.12
Neisseria gonorrhoeae (117) ----- 0.125
Neisseria meningitidis (11) ----- 0.001
Ureaplasma spp (22) ----- 0.25
E.coli (500) 62.70% 4
Klebsiella pneumoniae (389) 73.30% >4
Klebsiella oxytoca (111) 93.30% 0.12
Proteus mirabilis (211) ---- 2
Enterobacter spp (384) ----- 1
Citrobacter spp (178) ----- 2
Serratia spp (193) ----- 2
Pseudomonas aeruginosa (200) 54% >4
Acinetobacter baumanii- A. calcoaceticus (100) 47% >4
-----
Clostridium difficile (9) 0.03
-----
Clostridium perfringens (12) 0.008
-----
Bacteroides fragilis (48) 0.12
-----
Prevotella spp. (9) 4

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 -----
Peptostreptococcus spp. (15) 0.03
-----
Bacteroides thetaiotamicron (18) 0.5

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