Delafloxacin for the Treatment of Acute Bacterial Skin and Skin Structure Infections

Abstract

Objective: To review the microbiological activity, safety, and efficacy of the new fluoroquinolone delafloxacin for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Data Sources: A PubMed search from 1945 to September 2018 was done using the terms delafloxacin, acute bacterial skin and skin structure infections, skin and soft tissue infections, and fluoroquinolone. Additional sources include the Food and Drug Administration website, ClinicalTrials.gov, and the Melinta Therapeutics website. Study Selection and Data Extraction: The literature search was limited to those published in the English language and included in vitro and human studies that evaluated microbiological coverage, pharmacokinetics, pharmacodynamics, safety, and/or efficacy. Data Synthesis: Delafloxacin is a new fluoroquinolone with a unique structure for its class that covers both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas. This new antibiotic has demonstrated noninferiority to vancomycin plus aztreonam for the treatment of ABSSSIs in both an intravenous-only regimen and an intravenous to an oral regimen. Relevance to Patient Care and Clinical Practice: ABSSSIs are infections that are most often caused by Staphylococcus and represent one of the most common types of hospital infections. MRSA represents about half of all staphylococcal skin infections, and along with gram-negative infections, increase the rates of patient morbidity and health care costs. Delafloxacin is an additional treatment option that covers both of these types of microorganisms. Conclusions: Delafloxacin is a safe and effective treatment option for ABSSSIs, particularly in those with polymicrobial infections and those with MRSA.

Introduction

Acute bacterial skin and skin structure infections (ABSSSIs) were defined in 2013 by the US Food and Drug Administration (FDA) as cellulitis, erysipelas, major skin abscesses, and wound infections with a lesion surface area of at least 75 cm².¹ This new definition was implemented by the FDA, along with other recommendations for clinical trial development, in order to aid the expansion of new antimicrobials for ABSSSIs. Typically, the most common causative microorganism of ABSSSIs is Staphylococcus aureus.² Additionally, there has been a rise in infections caused by methicillin-resistant Staphylococcus aureus (MRSA), in both the community and hospital setting, with at least half of all staphylococcal infections being caused by MRSA.² Streptococci species, which is the most common cause of erysipelas, are also commonly implicated in ABSSSIs. Gram-negative species of microorganisms, while mainly occurring in surgical site infections, are a concern when treating polymicrobial skin infections. In 2005, 3.4 million emergency department visits in the United States were due to skin and soft tissue infections; studies have estimated that there has been an increase in ABSSSIs of about 30% to 50%, which has primarily been due to the spread of MRSA.^3,4 Morbidity and mortality rates also increase when there is increased exposure to MRSA, and those with advanced age or certain comorbidities such as diabetes are at an even higher risk.³

Delafloxacin is the newest addition to the fluoroquinolone class with a broad spectrum of activity and a uniquely beneficial side effect profile.⁵ Modifications at 3 locations (C7, C8, and N1) in the core structure account for delafloxacin’s differences from others in the fluoroquinolone class (Figure 1). Delafloxacin has the ability to form cleavable structures with DNA and topoisomerase IV or DNA gyrase and can subsequently inhibit the activity of gram-negative and gram-positive organisms. Unlike other members of the fluoroquinolone class, delafloxacin has equal affinity for both types of enzymes, which grants delafloxacin a broader spectrum of activity.

Figure 1.

Chemical structure of delafloxacin.

Data Selection

A PubMed search (1945 to September 2018) was conducted using the terms delafloxacin, acute bacterial skin and skin structure infections, skin and soft tissue infections, and fluoroquinolone. All articles in English were reviewed. Additional sources included ClinicalTrials.gov, the US FDA website, and the Melinta Therapeutics website.

Microbiological Coverage

The fluoroquinolone class, which includes agents such as ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin, has coverage to a wide range of gram-positive and gram-negative organisms; however, some agents do not cover certain gram-positive organisms. For example, ciprofloxacin does not have good coverage for methicillin-sensitive Staphylococcus aureus or Streptococcus pneumoniae, moxifloxacin does not have Pseudomonas coverage, and none cover MRSA. As mentioned previously, delafloxacin has a broad-spectrum activity that, unlike other members in the fluoroquinolone class, includes almost all gram-negative and gram-positive organisms including MRSA and anaerobes. Delafloxacin has shown potent activity against gram-positive organisms such as MRSA, methicillin-sensitive Staphylococcus aureus, Staphylococcus haemolyticus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus, and Enterococcus faecalis.⁶ It has also shown potent activity against gram-negative organisms such as Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, Neisseria gonorrhoeae, Enterobacteriaceae, and Pseudomonas aeruginosa. Additionally, delafloxacin has activity against anaerobes such as Bacteroides species, Prevotella species, Clostridium difficile, and Clostridium perfringens, and intracellular organisms such as Mycoplasma species, Ureaplasma species, and Chlamydia species. Delafloxacin has also been noted to have activity against Mycobacterium tuberculosis. Table 1 compares the minimum inhibitory concentration (MIC) ranges of delafloxacin, ciprofloxacin, and levofloxacin to a variety of microorganisms.^7-12

Table 1.

MIC Information Among Fluoroquinolones.^5,7-12

Pathogen	Fluoroquinolone	MIC (µg/mL)
		Susceptible	Intermediate	Resistant	MIC50	MIC90
MRSA	Delafloxacin	≤0.25	0.5	≥1	0.12	0.25
MSSA	Levofloxacin	≤1	2	≥4	0.5	2
	Ciprofloxacin	≤1	2	≥4	>128	>128
	Moxifloxacin	≤0.5	2	≥2	0.063	0.25
	Delafloxacin	≤0.25	0.5	≥1	0.008	0.03
Group A β-hemolytic Streptococci	Ciprofloxacin	≤1	2	≥4	0.5	0.5
	Levofloxacin	≤2	4	≥8	0.5	1
	Delafloxacin	≤0.06	—	—	0.008	0.015
	Moxifloxacin	—	—	—	≤0.12	0.25
Group B β-hemolytic Streptococci	Delafloxacin	≤0.06	0.12	≥0.25	0.008	0.03
	Levofloxacin	≤2	4	≥8	0.5	1
	Moxifloxacin	—	—	—	≤0.12	0.25
Enterococcus faecalis	Ciprofloxacin	≤1	2	≥4	0.5	1
	Levofloxacin	≤2	4	≥8	1	>4
	Moxifloxacin	≤1	2	≥4	0.5	16
	Delafloxacin	≤0.12	0.25	≥ 0.5	0.12	1
Enterobacteriaceae	Ciprofloxacin	≤1	2	≥4	≤0.03	>4
	Moxifloxacin	≤2	4	≥8	0.125	8
	Levofloxacin	≤2	4	≥8	≤0.12	>4
	Delafloxacin	≤0.25	0.5	≥1	0.12	0.25
Pseudomonas aeruginosa	Levofloxacin	≤2	4	≥8	0.5	>4
	Ciprofloxacin	≤1	2	≥4	0.25	>4
	Delafloxacin	≤0.5	1	≥2	0.25	>4
Haemophilus influenzae	Delafloxacin	—	—	—	≤0.001	0.004
	Ciprofloxacin	≤1	—	—	0.015	0.015
	Levofloxacin	≤2	—	—	0.015	0.03
Moraxella catarrhalis	Delafloxacin	—	—	—	0.008	0.008
	Ciprofloxacin	—	—	—	0.03	0.06
	Levofloxacin	—	—	—	0.06	0.06
Clostridium difficile	Delafloxacin	—	—	—	≤0.015	≤0.015
Levofloxacin	—	—	—	2	4

Abbreviations: MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus.

Pharmacokinetics/Pharmacodynamics

The bioavailability of delafloxacin is 58.8% and is not significantly altered by the ingestion of food.⁷ This is lower than other fluoroquinolones such as levofloxacin and ciprofloxacin, which have approximately 99% and 70% oral bioavailability, respectively.^8,10 C_max is achieved after 1 hour, and protein binding is 84%, primarily to albumin. Table 2 compares pharmacokinetic data of delafloxacin to other fluoroquinolones. Delafloxacin is predominantly excreted unchanged, and the primary metabolic pathway is glucuronidation via UGT1A1, 1A3, and 2B15. The half-life of the oral dosage form is 4.2 to 8.5 hours and the intravenous (IV) dosage form has a half-life of 3.7 hours. The IV dosage form is cleared 65% renally and 28% hepatically; the oral dosage form was excreted 50% renally and 48% hepatically. A phase 1 trial examining delafloxacin in patients with hepatic impairment found no differences in pharmacokinetic data among 4 groups with varying hepatic insufficiency, which included Child-Pugh classes A, B, C, and those with no hepatic impairment.¹³

Table 2.

Comparison of Pharmacokinetic Data Among Fluoroquinolones.^7-9

Comparator	Cmax (µg/mL)	Tmax (h)	AUC (µg h/mL)	t1/2 (h)	Oral Bioavailability
Delafloxacin 450 mg tablet Q12H	7.45 ± 3.16	1.00	30.8 ± 11.4	4.2-8.5	58.8%
Delafloxacin 300 mg IV Q12H	9.29 ± 1.83	1.0	23.4 ± 6.90	3.7	N/A
Levofloxacin 500 mg tablet Q24H	5.7 ± 1.4	1.1 ± 0.4	47.5 ± 6.7	7.6 ± 1.6	99%
Levofloxacin 500 mg IV Q24H	6.4 ± 0.8	—	54.6 ± 11.1	7.0 ± 0.8	N/A
Levofloxacin 750 mg tablet Q24H	8.6 ± 1.9	1.4 ± 0.5	90.7 ± 17.6	8.8 ± 1.5	99%
Levofloxacin 750 mg IV Q24H	12.1 ± 4.14	—	108 ± 34	7.9 ± 1.9	N/A
Ciprofloxacin 500 mg tablet Q12H	2.97	—	13.7	4	70%
Ciprofloxacin 750 mg tablet Q12H	3.59	—	31.6	4	70%
Ciprofloxacin 400 mg IV Q12H	4.56	—	12.7	4	N/A

Abbreviations: AUC, area under the curve; Q12H, every 12 hours; IV, intravenous; Q24H, every 24 hours.

IV delafloxacin is administered over 60 minutes at 300 mg every 12 hours (Q12H), and oral delafloxacin is dosed at one 450 mg tablet Q12H.⁷ Total dose exposure was tested in order to estimate an equivalent oral dose, and equivalence was found when the average was within an acceptable 80% to 125% interval.¹⁴ The free area under the curve (fAUC) for the 450 mg tablet was found to be 24.2 ± 6.45 h µg/mL and 26.7 ± 6.03 h µg/mL for 300 mg IV delafloxacin, and delafloxacin has shown to exhibit linear pharmacokinetics; steady state is achieved after 3 days of dosing and delafloxacin is dosed Q12H regardless of dosage form. In renal insufficiency (estimated glomerular filtration rate <30 mL/min), a dose reduction from 300 mg to 200 mg IV is recommended; the oral formulation of delafloxacin does not require adjustments.⁵ In those with end-stage renal disease, or those with an estimated glomerular filtration rate <15 mL/min, there is accumulation of the IV vehicle sulfobutylether-β-cyclodextrin and discontinuation of delafloxacin is recommended.⁷ In those undergoing hemodialysis, sulfobutylether-β-cyclodextrin is cleared at a rate of 4.74 L/h; over 4 hours of hemodialysis, 56.1% of this IV vehicle is recovered in the dialysate. No data on expression in breast milk have been reported.⁷

In older adults, C_max and AUC of delafloxacin were shown to be about 35% higher than in younger adults, but this was not found to be clinically significant as it was assumed to be due to lower creatinine clearances in this population.¹⁴ No other impact on delafloxacin’s pharmacokinetics in the elderly has been found.

The pharmacodynamic target of fluoroquinolone activity is the fAUC/MIC. A target of greater than 50 is typically effective for gram-positive pathogens, and >125 is the target for gram-negative organisms.¹³ It has been shown that for delafloxacin, the fAUC/MIC target for gram-positives may be different among phenotypes and infection sites.¹⁵ The fAUC/MIC target for Escherichia coli was found to be 14.5 for bacterial stasis and 26.2 for 1-log₁₀ reduction; the bacterial stasis target for Pseudomonas aeruginosa was found to be 3.8 and the 1-log₁₀ target was 5.0. Interestingly, these targets are much lower than the previously mentioned standard ranges for fluoroquinolones for these gram-negative organisms. No significant drug-drug interactions have been noted with delafloxacin.¹⁶

Safety and Adverse Effects

Fluoroquinolones as a class are known to have a variety of side effects that include impaired glycemic control, gastrointestinal effects such as Clostridium difficile diarrhea, seizures, tendon rupture, peripheral neuropathy, QT prolongation, and phototoxicity. A recent review examined these side effects in phase 3 trials in relation to study comparators.¹⁷ With regard to glycemic control, there were similar incidences of hyperglycemia or hypoglycemia between delafloxacin and treatment comparators (0.11% incidence rate of hyperglycemia or hypoglycemia in the delafloxacin group compared with 0.9% in the comparator groups). One incidence of mild severity Clostridium difficile diarrhea was reported in the delafloxacin group, while none were reported in comparator groups during these studies. It is thought that delafloxacin-related gastrointestinal side effects are due to direct irritation to the gastrointestinal tract, rather than an effect due to the fluoroquinolone structure.¹⁵ Treatment-related seizures were not noted in any group treated with delafloxacin, but 1 patient in a comparator group did have a seizure that was related to study treatment. Tendonitis occurred in 0.4% of patients in the delafloxacin group in phase 3 studies and no patients in the comparator group; there were also no reports of tendon rupture in any treatment group. Peripheral neuropathy related to study treatment occurred in 0.1% of delafloxacin patients and 0.3% of comparator patients; neuropathy was reported as either hypoesthesia, burning sensation, or paresthesia.

A randomized, placebo-controlled, crossover study examined the effects of delafloxacin on QTc interval.¹⁸ Fifty-two healthy subjects were randomized to receive either 300 mg IV delafloxacin, 900 mg IV delafloxacin, or 300 mg oral moxifloxacin; all groups also received either a placebo capsule or IV D5W in order to improve the blind. Neither dose groups of delafloxacin had shown an increase in QTc that broke 10 ms, which indicated no prolongation effect on QTc; however, this study only examined QTc after 1 dose of delafloxacin or moxifloxacin.

Photosensitivity is a side effect that has been noted to occur with agents of the fluoroquinolone class. A phase 1 study examined delafloxacin’s phototoxic potential at different doses and compared delafloxacin with the discontinued agent lomefloxacin, which has been reported to have the highest phototoxic potential of all the fluoroquinolones.¹⁹ Fifty-two subjects were randomized to receive either 200 mg delafloxacin, 400 mg delafloxacin, 400 mg lomefloxacin, or placebo. Delafloxacin was not found to show any phototoxic potential, just as gatifloxacin and moxifloxacin have not been linked to phototoxic events in past studies.

Clinical Trials

Phase 2 Studies

Delafloxacin was compared with linezolid and vancomycin for the treatment of ABSSSIs in a randomized phase 2 study done by Kingsley et al.²⁰ This trial was a multicenter, stratified, double-blind trial that randomized 256 patients to either 300 mg twice daily of IV delafloxacin, 600 mg twice daily of IV linezolid, or 15 mg/kg twice daily of IV vancomycin. The most common infections were cellulitis/erysipelas (44.9%), major cutaneous abscess (28.5%), and wound infection (25%). Delafloxacin had a cure rate of 70.4%, linezolid’s cure rate was 64.9%, and vancomycin’s cure rate was 54.1%. Differences in cure rates between delafloxacin and linezolid were not statistically significant (P = .496), but differences between delafloxacin and vancomycin showed delafloxacin to have a significantly better cure rate than vancomycin (P = .031; number needed to treat = 18). Delafloxacin was also reported to have a significantly better reduction in total erythema area than vancomycin (P = .028). Average treatment duration was 7.6 days for the delafloxacin group, 7.4 days for the linezolid group, and 7.8 days for the vancomycin group. In a post-analysis, it was also shown that obese patients had a statistically significant higher cure rate with delafloxacin in comparison to vancomycin (78.8% in the delafloxacin group and 48.8% in the vancomycin group, P = .009), but this was not the case in nonobese patients (64.6% in the delafloxacin group and 57.9% in the vancomycin group). There was also a higher cure rate among weight groups who received delafloxacin (64.6% in the nonobese group and 78.8% in the obese group). Rates of nausea, diarrhea, and vomiting were also reported more frequently in the delafloxacin group than the vancomycin group.

Another phase 2 study compared 2 different doses of delafloxacin to tigecycline.²¹ This randomized, double-blind multicenter trial included 150 patients with complicated skin and skin structure infections, which they defined as infections involving the subcutaneous tissues or requiring surgical intervention. Patients were randomized in a 1:1:1 fashion to receive either 300 mg twice daily of IV delafloxacin, 450 mg twice daily of IV delafloxacin, or 100 mg daily of IV tigecycline for 5 to 14 days. Clinical cure rates were similar among the 3 groups; 94.3% in the 300 mg delafloxacin group, 92.5% in the 450 mg delafloxacin group, and 91.2% in the tigecycline group (P > .05). No infusion site reactions were reported in the 300 mg delafloxacin group, but there were 2 discontinuations in the 450 mg delafloxacin group and 3 discontinuations in the tigecycline group due to adverse events. Only 1 serious adverse event related to study drug occurred and was reported to be a generalized seizure in the 450 mg delafloxacin group.

Phase 3 Studies

A randomized, multicenter, multinational, stratified, double-blind phase 3 trial was reported by Pullman et al, comparing IV delafloxacin to vancomycin plus aztreonam for ABSSSIs.²² Patients were eligible for inclusion if they were 18 years of age or older with a diagnosis of ABSSSI. ABSSSIs were classified as either cellulitis/erysipelas, a wound infection, a major cutaneous abscess, or burn infection with an area of at least 75 cm² of erythema and at least 2 signs of systemic infection. Measurement of erythema size was done by digital planimetry, which involves tracing the margins of a wound and calculating its area.²³ If patients had received systemic antibiotic therapy in the 14 days before enrollment they were excluded, unless the antibiotic was given for 48 hours for treatment of an ABSSSI, but the infection progressed, or the antibiotic given did not have activity against microorganisms that commonly cause ABSSSI, or if the antibiotic was given in a single dose and was short acting. Six hundred sixty-six patients across 34 centers in 7 countries were randomized in a 1:1 fashion to receive either 300 mg IV delafloxacin or 15 mg/kg IV vancomycin plus 2 g aztreonam Q12H. Aztreonam added to vancomycin therapy for gram-negative coverage but was discontinued if baseline cultures did not show gram-negative organisms. The FDA defines a primary efficacy endpoint as at least a 20% reduction in erythema area at 48 to 72 hours after treatment initiation. Clinical failure also defined as either a less than 20% reduction in erythema area, administration of rescue, or any other non-study antibiotics, unplanned surgical intervention, or death within 74 hours after treatment initiation. A total of 74.2% of patients had a positive culture, and Staphylococcus aureus was isolated in 65.4% of the delafloxacin group and 66.8% of the vancomycin/aztreonam group. MRSA was identified in 32.1% of the delafloxacin group and 36.8% of the vancomycin/aztreonam group. A total of 78.2% of the delafloxacin group and 80.9% of the vancomycin/aztreonam group met the primary efficacy endpoint and therefore met noninferiority (95% confidence interval [CI] = −8.78 to 3.57). Duration of treatment for the delafloxacin group was 5 days, and for the vancomycin/aztreonam group, it was 5.5 days. A total of 47.5% of patients in the delafloxacin group experienced at least 1 treatment emergent adverse effect (TEAE) in comparison to 59.2% of the vancomycin/aztreonam group. Most TEAEs in the delafloxacin group were nausea and diarrhea (12%), and there were no reports of Clostridium difficile diarrhea, tendonitis/tendon rupture, peripheral neuropathy, or myopathy.

When comparing the 2 treatment groups, both had almost identical categories of ABSSSI, with 38.7% of the delafloxacin group and 38.9% of the vancomycin/aztreonam group having cellulitis/erysipelas. There were also 35% of the delafloxacin group and 35.3% of the vancomycin/aztreonam group that had a wound infection. Groups differed slightly in baseline erythema and induration size; the delafloxacin group had an average erythema size of 294.8 ± 308.34 cm² and an average induration size of 94.1 ± 208.66 cm², while the vancomycin/aztreonam group had an average erythema size of 319.1 ± 314.03 cm² and an average induration size of 120.7 ± 219.6 cm². Gram-negative organisms were isolated in 10.7% of the delafloxacin group and 12.9% of the vancomycin/aztreonam group.

Recently, O’Riordan et al compared an IV to an oral regimen of delafloxacin to vancomycin plus aztreonam for the treatment of ABSSSIs in another phase 3 trial.²⁴ This multicenter, multinational, stratified, randomized, double-blind trial included patients who were 18 years of age or older with a diagnosis of ABSSSI, which was defined as cellulitis/erysipelas, a wound infection, major cutaneous abscess, or burn infection. Eight hundred fifty patients, the majority of which were Caucasian males, were randomized to either delafloxacin or vancomycin plus aztreonam, all with renal dose adjustments if required. For those with a creatinine clearance greater than 29 mL/min, 300 mg IV delafloxacin Q12H was given for 6 doses, and then a switch to 450 mg per os (by mouth) Q12H was made. For those with a creatinine clearance between 15 and 20 mL/min, the IV dose was reduced to 200 mg Q12H, but the oral dose remained the same. A total of 47.8% of the delafloxacin group and 48.2% of the vancomycin/aztreonam group were diagnosed with cellulitis/erysipelas, and in both groups, the percentage of those with wound infections was less than 1%. The FDA and European Medicines Agency’s primary efficacy points were identical to that in the previously mentioned phase 3 study. A total of 842 patients received at least 1 dose of study drug and were hence included in the intent-to-treat (ITT) analysis; 552 of these patients also had a pathogen identified at baseline and were then included in the microbiological ITT (MITT) population. A total of 58.2% of the delafloxacin group and 57.0% of the vancomycin/aztreonam group had Staphylococcus aureus isolated, with 24% and 18.1% of these isolated being MRSA, respectively. In the ITT population, there was 83.7% of the delafloxacin group and 80.6% of the vancomycin/aztreonam group that were classified as responders (95% CI = −2.0 to 8.3), meaning delafloxacin met noninferiority. It was also noted there was a similar efficacy for delafloxacin in the MITT population. Additionally, delafloxacin met the European Medicines Agency’s primary efficacy endpoint with a cure rate of 57.7% compared with 59.7% in the vancomycin/aztreonam group (95% CI = −8.6 to 4.6). TEAEs, most mild in severity, occurred in 43.6% of the delafloxacin group and 39.3% of the vancomycin group, but there was one incidence of Clostridium difficile diarrhea in the delafloxacin group. There were no cases of tendinitis, tendon rupture, or myopathy but 1 case of paresthesia in each treatment group. Both treatment groups had an average duration of therapy of 6.5 days.

Treatment groups in this study were well matched; however, both groups had a large majority of patients who were Caucasian males, and patients with diabetes were low in both groups (12.5% in the delafloxacin group and 12.6% in the vancomycin group). Gram-negative organisms were isolated in 20.7% of the identified pathogens, but specific gram-negative pathogens per study group were not reported. Patients were also stratified for obesity, as previous studies of delafloxacin have shown differences in this patient group, but the rate of cure and success were similar between delafloxacin and vancomycin plus aztreonam groups.

Table 3 summarizes phase 2 and 3 trials of delafloxacin.

Table 3.

Summary of Phase 2 and 3 Trials.

Study	N	Design	Inclusion	Exclusion	ABX Regimen	Results	Limitations
Kingsley et al20 (Phase 2)	256	MC, S, R, DB	Over 18 years of age, diagnosable ABSSSI, ≥75 cm2 induration or erythema, and planimetry plus lymph node enlargement or one sign of systemic infection	Hypersensitivity/allergy to study drugs, concurrent conditions, inadequate arterial blood supply, immunocompromise, hypertension, weight >140 kg, antibiotic within 24 hours	300 mg DFX IV, 600 mg LNZ IV, 15 mg/kg VNC IV, 5 to 14 days	Cure rate DFX vs LNZ, P = .496 Cure rate DFX vs VNC, P = .031 Post hoc obese cure rate DFX vs VNC, P = .009 Total erythema reduction DFX vs VNC, P = .028	Exclusion of >140 kg patients, more leniency with participation in other studies within 24 hours (accounting for <30% of patients), almost 60% men
O’Riordan, et al21 (Phase 2)	150	R, DB, MC	Over 18 years of age, cSSSI, infection must be 1 of 3 predetermined types	Hypersensitivity/allergy to study drugs, pregnancy/lactation, diabetic foot ulcers, osteomyelitis, septic arthritis, prosthetic device infections, necrotizing fasciitis, significantly impaired arterial blood supply	300 mg DFX IV Q12H, 450 mg DFX IV Q12H, 100 mg TG IV qd for 5 to 14 days	Clinical cure rate: DFX 300 mg: 94.3%; DFX 450 mg: 92.5%; TG 50 mg: 91.2%; No statistical difference	Should have been compared with standard of care rather than TG
Melinta Therapeutics25 (Phase 3)	660	R, PA, DB	Over 18 years of age, ABSSSI, ≥75 cm2 erythema, ≥2 signs of systemic infection	Hypersensitivity/allergy to study drugs, pregnancy/lactation, other skin conditions, antibiotic in the past 14 days	DFX 300 mg IV Q12H, VNC 15 mg/kg IV + 2 g AZ Q12H for 5 to 14 days	≥20% erythema reduction in 24 to 48 hours: 95% CI (−3.57 to 8.78) = noninferior	One dose of some antibiotics may have been effective
Melinta Therapeutics27 (Phase 3)	850	R, PA, DB	Over 18 years of age, ABSSSI, ≥75 cm2 erythema, ≥2 signs of systemic infection	Hypersensitivity/allergy to study drugs, pregnancy/lactation, other skin conditions, antibiotic in the past 14 days	DFX 300 mg IV Q12H then DFX 450 mg PO Q12H, VNC 15 mg/kg IV + 2 g AZ Q12H for 5 to 14 days	≥20% erythema reduction in 24 to 48 hours: 95% CI (−2.0 to 8.3) = noninferior	One dose of some antibiotics may have been effective

Abbreviations: MC, multicenter; S, stratified; R, randomized; DB, double blind; ABSSSI, acute bacterial skin and skin structure infections; DFX, delafloxacin; IV, intravenous; LNZ, linezolid; VNC, vancomycin; cSSSI, complicated skin and skin structure infections; Q12H, every 12 hours; TG, tigecycline; qd, every day/daily; PA, parallel assignment; AZ, aztreonam; CI, confidence interval; PO, per os (by mouth).

Other Ongoing Trials

At this time, delafloxacin is only approved for ABSSSIs; however, additional indications for community-acquired pneumonia as well as complicated urinary tract infections are currently being tested.²⁴ Currently, there is an ongoing study comparing delafloxacin with moxifloxacin for the treatment of community-acquired pneumonia.²⁶ There was also one study terminated regarding the treatment of Neisseria gonorrhoeae due to data indicating that it may not be sufficient for some patients despite an in vitro study that showed potential for efficacy.^27,28

Relevance to Patient Care and Clinical Practice

As MRSA-related infections are on the rise, new treatment options are important in order to reduce morbidity, mortality, and health care costs associated with these infections. The Infectious Diseases Society of America guideline for the management of skin and soft tissue infections, which was last updated in 2014, recommends using either vancomycin, linezolid, clindamycin, daptomycin, ceftaroline, doxycycline, minocycline, or trimethoprim-sulfamethoxazole for MRSA infections.²⁹ At this time, vancomycin is the preferred IV treatment option for MRSA infections due to its high level of efficacy and the fact that newer agents have yet to show superiority to vancomycin with regard to clinical cure rates.³⁰ Delafloxacin has shown activity against MRSA, but it also has not shown superiority for treating MRSA infections. Delafloxacin is also active against other gram-positive organisms, gram-negative organisms such as Pseudomonas, and anaerobes. Evidence has shown that in both an IV-only regimen and an IV to an oral regimen, delafloxacin is noninferior to vancomycin plus aztreonam for the treatment of ABSSSI and has minor adverse effects. Delafloxacin’s broad spectrum of activity, oral and IV formulations, and safety profile offer therapeutic advantages in comparison to other members of the fluoroquinolone class. Additionally, its advantages could prove beneficial when compared with agents that are currently recommended for the treatment of ABSSSI, especially polymicrobial and complicated diabetic foot infections. As new clinical trials are underway, delafloxacin could also potentially be a valid treatment option for community-acquired pneumonia or urinary tract infections. However, the cost of delafloxacin (average wholesale price: $159 per 300 mg IV solution and $85 per 450 mg tablet) could hinder its use, especially when compared with existing treatment options on the market with well-established clinical evidence and lower prices.³¹ For complicated polymicrobial skin infections, especially those due to MRSA or Pseudomonas aeruginosa, diabetic foot infections, infections in IV drug users, infections in those with neutropenia, or in those with a severe β-lactam allergy, delafloxacin can be a reasonable option if monotherapy is preferred.

Summary

Delafloxacin is a newly approved fluoroquinolone with broad-spectrum activity and a favorable side effect profile, especially when compared with other members in its class. Renal dose adjustments are required with IV delafloxacin therapy and a target goal fAUC/MIC should be maintained. As studies have shown, delafloxacin is an agent with good efficacy and minor adverse effects when used to treat ABSSSIs.