Pharmacodynamics
Delafloxacin had potent in vitro activity against contemporary (2014–2016) bacterial isolates frequently associated with ABSSSIs from European [4] and US [5, 6] medical centres participating in the SENTRY surveillance program. The drug had potent activity against Staphylococcus aureus (n = 903/3163 European/US; MIC90 0.25 µg/mL) and coagulase-negative staphylococci (CoNS [n = 165/228 European/US] MIC90 0.5 µg/mL) including fluoroquinolone (levofloxacin) and methicillin-resistant strains (MIC90 ≤1 µg/mL). Delafloxacin had an MIC90 of 0.03 µg/mL against β-haemolytic streptococci (n = 254/967 European/US) and viridans group streptococci (n = 27/133 European/US). The drug had an MIC90 of 1 µg/mL against Enterococcus faecalis (n = 173/235), >4 and 2 µg/mL against European (n = 867) and US (1325) Enterobacteriaceae isolates, respectively, and >4 and 4 µg/mL against European (n = 275) and US (224) Pseudomonas aeruginosa isolates, respectively. Delafloxacin had considerably greater in vitro activity than levofloxacin against E. faecalis, Enterobacteriaceae and P. aeruginosa (levofloxacin MIC90 >4 µg/mL) in these studies [4,5,6]. Delafloxacin had an MIC90 of 0.25 µg/mL against S. aureus isolates (n = 685, including 294 methicillin-resistant S. aureus (MRSA) and 232 levofloxacin-resistant strains) collected from patients with ABSSSIs participating in two phase III trials [7].
Delafloxacin has demonstrated bactericidal activity in vitro against MRSA [7, 8] with minimum bactericidal concentrations (MBC) of 0.008, 0.5 and 8 µg/mL against MRSA strain 110 (levofloxacin susceptible), 124 (triple mutant) and 165 (quadruple mutant), respectively, compared to 0.5, 8 and >32 µg/ml for levofloxacin. Bactericidal activity was observed at 6 h for most concentrations of delafloxacin and levofloxacin against MRSA strain 110; delafloxacin at 16 times MIC killed MRSA strain 124 more quickly than levofloxacin at the same concentration, and was bactericidal at 16 and 32 times MIC against MRSA strain 165 at 24 h [8]. In two global phase III trials, high rates of microbiological response (>98% eradication rates) were seen against levofloxacin nonsusceptible S. aureus and MRSA isolates and against isolates with mutations in the Quinolone Resistance Determining Region (QRDR) [7].
Delafloxacin had potent activity against S. aureus (n = 4 [including 2 MRSA strains]), Streptococcus pneumoniae (n = 4 [including 2 penicillin-resistant strains]), and Klebsiella pneumoniae (n = 4 [including 3 extended-spectrum β-lactamase-producing (ESBL) strains]) in vivo in a neutropenic murine lung infection model. Increasing 0.03 to 160 mg/kg doses of delafloxacin were administered once every 6 h to infected mice with treatment outcome measured according to the organism burden in the lung (colony forming units) after 24 h. The median free drug area under the time–concentration curve (AUC)/MIC targets associated with net stasis were 1.42 for S. aureus, 0.56 for S. pneumoniae and 40.3 for K. pneumoniae; 1-log kill targets were 7.92, 3.36 and 55.2, respectively [9].
Delafloxacin had no clinically relevant effect on the QT/QTc interval after administration of therapeutic (300 mg) and supratherapeutic (900 mg) IV doses in thorough QT studies in volunteers (n = 52 and 51, respectively) [10].
Delafloxacin showed no clinically significant phototoxic potential at all wavelengths tested after 6 days’ administration of 200 or 400 mg/day oral doses in volunteers (n = 12 and 11, respectively) [11].
Pharmacokinetics
Administration of single 300–1200 mg IV doses of delafloxacin to volunteers (n = 52) was associated with proportionally increasing maximum plasma concentrations (Cmax) and more than proportional increases in AUC. The mean terminal half-life was ≈12 h and steady-state volume of distribution (Vd) was ≈35 litres. Cmax and AUC12 were 9.29 μg/mL and 23.4 μg·h/mL, respectively, after administration of IV delafloxacin 300 mg twice daily for 14 days to volunteers (n = 7). Minimal accumulation was observed (accumulation ratio 1.09) [12].
The equivalence of IV and orally administered delafloxacin has been evaluated in an open two period, two sequence crossover study in volunteers (n = 56). Participants were randomised to receive a single 450 mg oral dose and a single 300 mg IV infusion of the drug. Geometric least squares mean AUC∞ was considered equivalent between the 2 dosage forms (22.97 and 26.2 μg·h/mL, respectively [percent ratio 87.68]), however Cmax (5.8 and 10.51 μg/mL, respectively [percent ratio 55.16]) was not. These data support the use of both formulations in IV to oral switch settings in phase III clinical trials [12].
Oral administration of single 50–1600 mg doses of delafloxacin to male volunteers (n = 56) was associated with a dose-normalised decrease in Cmax with increasing dose; AUC∞ increased proportionally with doses ≥200 mg. Mean half-life was ≤2.5 h after administration of 50 and 100 mg doses and 5.9–7.7 h with doses ≥200 mg. The proportion of drug excreted unchanged in urine decreased with increasing dose (from 35.6% at 50 mg to 12.8% at 1600 mg) [13].
Dose-normalised Cmax and AUC decreased with increasing dose after administration of multiple oral delafloxacin 100–1200 mg once daily for 5 days to volunteers (n = 37). AUC values on day 5 were higher than on day 1 but accumulation was minimal (mean accumulation ratio ≤1.24). Steady state was achieved after ≈3 days. Mean half-life was 4.2 h in the 100 mg/day group and 7.4–8.5 h in the ≥200 mg/day groups at day 5 [13].
Delafloxacin Cmax and AUC∞ were significantly (p ≤ 0.001) higher in elderly (n = 12) than in young volunteers (n = 28) after administration of a single 250 mg dose which appeared to be related to decreased creatinine clearance in the elderly cohort. The pharmacokinetic profile of the drug was similar in men and women in both the elderly and young cohorts [13].
Administration of delafloxacin 900 mg in a formulated tablet with a high fat meal was associated with a reduction in Cmax compared with fasting conditions but this did not affect total exposure [13].
The pharmacokinetic properties of delafloxacin were similar in subjects with mild, moderate, and severe hepatic impairment (Child–Pugh class A, B, and C, respectively) compared with matched volunteers with normal hepatic function after administration of a single 300 mg IV dose, indicating that dose adjustment of delafloxacin is not necessary in patients with hepatic impairment [14].
The mean total exposure (AUCt) of delafloxacin after a single oral 400 mg dose was ≈1.5-fold higher in patients with moderate (estimated glomerular filtration rate [eGFR] 31–50 mL/min/1.73 m2) and severe (eGFR 15–29 mL/min/1.73 m2) renal impairment compared to volunteers. However, total systemic exposures of delafloxacin in subjects with mild renal impairment (eGFR 51–80 mL/min/1.73 m2) was similar to that in volunteers.
The IV vehicle sulfobutylether-β-cyclodextrin (SBECD) accumulates in patients with moderate or severe renal impairment, or end stage renal disease (ESRD) on haemodialysis, with AUC increasing 2-, 5-, 7.5- and 27-fold, respectively, after administration of IV delafloxacin between 1 h before and 1 h after haemodialysis compared to volunteers. In patients with ESRD undergoing haemodialysis, SBECD is dialyzed with a clearance of 4.74 L/h. When haemodialysis occurred 1 hour after infusion of delafloxacin in patients with ESRD, the mean fraction of SBECD recovered in the dialysate was 56.1% over ≈4 h [1]. It is recommended that the dosage of IV delafloxacin be reduced to 200 mg every 12 h or 200 mg every 12 h with a switch to 450 mg orally at the discretion of the physician. Administration to patients with ESRD is not recommended as there are insufficient data to recommend a dose regimen for this patient population [1].
Features and properties of delafloxacin
Alternative names
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ABT-492, Baxdela, RX-3341, RX-3341-83, WQ-3034
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Class
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Antibacterials, azetidines, fluoroquinolones, pyridines, small molecules
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Mechanism of Action
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DNA gyrase inhibitors; DNA topoisomerase IV inhibitors
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Route of Administration
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Oral, IV
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Pharmacodynamics
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MIC90 0.25 µg/mL against Staphylococcus aureus, 0.5 µg/mL against coagulase-negative staphylococci, 0.03 µg/ml against β-haemolytic and viridans group streptococci, 1 µg/mL against Enterococcus faecalis, and >2 µg/mL against Enterobacteriaceae and Pseudomonas aeruginosa
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Pharmacokinetics
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Cmax 7.45/9.29 µg/mL, AUC 30.8/23.4 μg·h/mL, CL/F/CL 16.8/13.8 L/h at steady state (oral/IV)
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Adverse events
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Most frequent
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Nausea, diarrhoea
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Occasional
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Headache, vomiting
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Rare
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ATC codes
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WHO ATC code
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J01M-A (fluoroquinolones)
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EphMRA ATC code
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J1G (fluoroquinolones)
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Chemical name
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1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid
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Drug Interactions
Coadministration of midazolam and delafloxacin in volunteers was not associated with clinically relevant changes in the pharmacokinetic profile of midazolam indicating delafloxacin can be co-administered with cytochrome P4503A substrates without regard for drug–drug interactions [15].
Oral delafloxacin should be given at least 2 h before or 6 h after antacids containing aluminium or magnesium, sucralfate, metal cations such as iron, multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations as these may interfere with the absorption of delafloxacin, resulting in sub-optimal systemic concentrations [1].
Therapeutic Trials
Phase III
Delafloxacin had similar efficacy to vancomycin plus aztreonam as treatment for ABSSSIs in two phase III multicentre double-blind trials. In study 302 (NCT01811732) patients were randomised to IV delafloxacin 300 mg twice daily (n = 331) or IV vancomycin 15 mg/kg twice daily plus twice daily aztreonam (n = 329) for 5–14 days; 19% of patients received a single dose of short-acting antibiotic prior to enrolment. Pathogens were identified at baseline in 490 patients, most frequently S. aureus [1, 16]. An objective clinical response (≥20% reduction in lesion size with no further antibiotics, major procedures or death) was seen in 78.2 and 80.9% of delafloxacin and vancomycin plus aztreonam recipients, respectively, 48–72 h after completing treatment. Complete resolution of signs and symptoms (investigator-assessed cure) was seen in 81.6 and 83.3% of patients in the respective treatment groups (ITT analysis; 96.7 and 97.5% of patients in the clinically evaluable population) at follow up (day 13–15). Similar success rates were seen at late follow-up (day 21–28) [1]. Documented or presumed bacterial eradication (microbiological response) was observed in 97.8 and 98.4% of delafloxacin and vancomycin plus aztreonam recipients, respectively, including 100 and 98.5% of patients with MRSA [16].
In study 303 (NCT01984684) patients were randomised to IV delafloxacin 300 mg twice daily for 3 days then oral delafloxacin 450 mg (n = 423), or vancomycin 15 mg/kg IV plus aztreonam (n = 427) for 5–14 days. Pathogens were identified at baseline in 552 patients, most frequently S. aureus [1, 17]. An objective clinical response (as per study 302 above) was seen in 83.7 and 80.6% of delafloxacin and vancomycin plus aztreonam recipients, respectively, 48–72 h after commencing treatment. Complete resolution of signs and symptoms (investigator-assessed cure) was seen in 87.2 and 84.8% of patients in the respective treatment groups (ITT analysis; 96.0 and 97.0% of patients in the clinically evaluable population) at follow up (day 13–15). Similar success rates were seen at late follow-up (day 21–28) [1]. Documented or presumed eradication of MRSA was observed 96 and 97% of delafloxacin and vancomycin plus aztreonam recipients, respectively [17].
Phase II
Delafloxacin had similar efficacy to tigecycline (study 201 [NCT0719810]) [18] as treatment for a variety of complicated skin and skin-structure infections and was similar to linezolid and superior to vancomycin as treatment for ABSSSI (study 202 [NCT01283581]) [19] in randomised double-blind phase II trials.
Study 201 compared IV treatment with delafloxacin 300 or 450 mg once every 12 h, or IV tigecycline (100 mg initial dose then 50 mg once every 12 h) for 12–14 days in patients with various complicated skin and skin-structure infections (wound infections following surgery, trauma, burns, or animal/insect bites, abscesses, and cellulitis). Clinical cure (completely resolved or improved to the extent that additional treatment was not necessary) was achieved in 33 of 35 (94.3%), 37 of 40 (92.5%) and 31 of 34 (91.2%) evaluable patients, in the delafloxacin 300 and 450 mg twice daily groups and the tigecycline group, respectively, at the test-of-cure visit 14–21 days after the final dose of study drug. Infections caused by S. aureus (including MRSA) were effectively treated in all three groups and microbiological eradication rates were similar to clinical response by pathogen rates [18].
Study 202 compared delafloxacin 300 mg, linezolid 600 mg and vancomycin 15 mg/kg, all administered IV twice daily for 5–14 days, in patients with ABSSSIs. Investigator-assessed intention-to-treat clinical cure (complete resolution of ABSSSI signs and symptoms) at follow-up (day 13–15) was achieved in 57 of 81 (70.4%) delafloxacin recipients compared to 53 of 98 (54.1) vancomycin (p < 0.05) and 50 of 77 (64.9%) linezolid recipients. The microbiological response was presumed eradicated in 88.2, 80.8 and 82.1% of microbiologically evaluable delafloxacin, vancomycin and linezolid recipients, respectively. Apart from one linezolid recipient in whom response was documented persistent, all other responses were presumed persistent [19].
Key clinical trials of delafloxacin (Melinta Therapeutics)
Drugs(s)
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Indication
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Phase
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Status
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Location(s)
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Identifier
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---|
Delafloxacin, tigecycline
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Complicated skin infections
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II
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Completed
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US, Puerto Rico
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NCT00719810
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Delafloxacin, linezolid, vancomycin
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Bacterial skin infections
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II
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Completed
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US
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NCT01283581
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Delafloxacin, ceftriaxone
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Uncomplicated gonorrhoea
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III
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Terminated
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US
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NCT02015637
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Delafloxacin, vancomycin, aztreonam
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Skin and skin structure infections
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III
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Completed
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Multinational
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NCT01984684
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Delafloxacin, vancomycin, aztreonam, placebo
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Skin and skin structure infections
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III
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Completed
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Multinational
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NCT01811732
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Delafloxacin, moxifloxacin, linezolid
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Community-acquired bacterial pneumonia
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III
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Recruiting
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Multinational
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NCT02679573
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Adverse Events
Adverse events occurring in at least 2% of delafloxacin recipients participating in the 2 phase III ABSSSI trials included nausea (8 and 6% of delafloxacin [n = 741] and vancomycin plus aztreonam [n = 751] recipients, respectively), diarrhoea (8 and 3%), headache (3 and 6%), transaminase elevations (3 and 4%; pooled reports; includes hypertransaminasaemia, increased transaminases, and increased ALT and AST) and vomiting (2 and 2%) [1]. No cases meeting the Hy’s law definition have been reported with delafloxacin in clinical trials [17]. Adverse events occurring at a rate of <2% in delafloxacin recipients included sinus tachycardia, palpitations, bradycardia, tinnitus, vertigo, blurred vision, infusion site extravasation, infusion site reactions (including bruising, discomfort, oedema, erythema, irritation, pain, phlebitis, swelling and thrombosis), abdominal pain, dyspepsia, hypersensitivity, Clostridium difficile infection, fungal infection, oral candidiasis, vulvovaginal candidiasis, hyperglycaemia, hypoglycaemia, myalgia, dizziness, hypoesthesia, paraesthesia, dysgeusia, presyncope, syncope, anxiety, insomnia, abnormal dreams, renal impairment or failure, pruritus, urticaria, dermatitis, rash, flushing, hypotension, hypertension and phlebitis [1].
Prescribing information for delafloxacin includes a boxed warning that fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions including tendinitis and tendon rupture, peripheral and central nervous system effects, and states that delafloxacin should be discontinued in patients who experience any of these. Use of delafloxacin should also be avoided in patients with myasthenia gravis [1].
Ongoing Clinical Trials
A phase III study (DEFINE-CABP; NCT02679573) comparing delafloxacin and moxifloxacin as treatment for community-acquired bacterial pneumonia is currently recruiting patients.