- ABSSSIに対して、 vancomycin plus aztreonamと同等。The primary endpoint was investigator assessed response based on resolution of signs and symptoms at 48-72 hours.
- 副作用は、胃腸系 : 吐き気7.7％、下痢7.7％、嘔吐2.4％
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.
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 thisapproval 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
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.
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)
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 vitroactivity 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.
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 duringthe 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
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
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.
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
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 asP. 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.
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.
21.O’Riordan W, McManus A, Teras J, Poromanski I, Cruz-Saldariagga M, Quintas
M,Lawrence L, Liang SJ, Cammarata S, PROCEED Study Group; A comparison of the efficacy and safety of intravenous followed by oral delafloxacin with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections: a phase 3, multinational, double-blind, randomized study,Clinical Infectious Diseases, 2018 ciy165, https://doi.org/10.1093/cid/ciy165 ( in press)
22.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 https://doi.org/10.1093/jac/dkx329
23.McCurdy, S, Lawrence L, Quintas M, Woosley L, Flamm R, Tseng C, Cammarata S. 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. September 2017 61:9 8 e00772-17
24.Litwin JS, Benedict MS, Thorn MD, Lawrence LE, Cammarata SK, et al. A thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization. Antimicrob Agents Chemother 2015; 59: 3469-3473.
25.So W, Crandon JL, Nicolau DP. Effects of urine matrix and pH on the potency of delafloxacin and ciprofloxacin against urogenic Escherichia coli and Klebsiella pneumoniae. J Urol 2015; 194:563-70.
26.Ruiz J, Pons MJ, Gomes C. Transferable mechanisms of quinolone resistance. Intern J Antimicrob Agents 2012; 40:196-203
27.Delafloxacin (Baxdela)–A new fluoroquinolone antibiotic. The Medical letter on Drugs and Therapeutics. 2018; 50:4951