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

O’Riordan, William; McManus, Alison J.; Teras, J; Poromanski, I; Cruz-Saldariagga, Maria; Quintas, Manuel Rodrigues; Lawrence, Laura; Liang, ShuJui; Cammarata, Sue; Chaparro, Gustavo Jorge; Frassone, Natalia Elizabeth; Morera, Graciana; Freire, Antonio; Stobbe, Júlio César; Dimov, R; Ninov, Borislav; Rusev, P.; Simeonov, S; Todorov, Georgi Vasilev; Godoy, Jorge Manuel Perez; Lind, Jaak; Tein, Andres; Uksov, Andrei; Akhalaia, Roland; Gotsadze, Erekle; Kashibadze, Kakhaber; Vashadze, Jano; Együd, Katalin; Horváth, Zsolt; Kemény, Lajos; Kövágó, Levente; Oláh, Tibor; Cho, Yong Kyun; Choi, Seong-Ho; Choi, Won Seok; Chong, Yong Pill; Kim, Jong Hun; Kim, Shin‐Woo; Kim, So Hyun; Gardovskis, Jānis; Lovcinovskis, Viktors; Nalivaiko, Maris; Pupelis, Guntars; Noriega, Eduardo Rodríguez; Perez, N.; Ortiz, Adrian Camacho; Guţu, Eugen; Revencu, Sergiu; Ungureanu, Sergiu; Cosavalente, Luis A Camacho; Medina, Jaime Ismael Soria; Cruz, María; Reyna, Oscar G. Pamo; P, Leiva; Ciurea, Marius Eugen; Florea, I; Giuglea, Carmen; Marinescu, Silviu Adrian; Morariu, Silviu Horia; Orăsan, Remus Ioan; Crainiceanu, Petrisor Z; Chen, Yen-Hsu; Chuang, Yin-Ching; Green, Sinikka Liisa; Kingsley, Jeffrey K; Miller, Loren G.; Houghton, Robert; Willits, Verne Leroy; Mannis, Steven Hugh; Stucke, Sheri; Rives, Peter; Hansen, Eric; Pecci, Pietro Giuseppe; Villar, Hermilito L; Beasley, Richard; Giordano, Philip; Pullman, John; Wan, Chok Ping; Shah, Shaukat; Oguchi, Godson; Birch, Thomas; Dar, Sadi M; Baynton, Barr; Hoppers, Melanie

doi:10.1093/cid/ciy165

Cited by 82 publications

(96 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Most AEs were mild to moderate in intensity. Relative to IV delafloxacin, oral delafloxacin was not associated with an increase in gastrointestinal events, and the pattern of treatment-emergent adverse events was similar to those of the IV formulation in the 2 phase III trials [ 7 , 8 ]. Delafloxacin had a low rate of discontinuations due to treatment-related adverse events (TRAEs; <1%).…”

Section: Resultsmentioning

confidence: 93%

“…The incidence of serious adverse events (SAEs) was similar between delafloxacin and comparators ( Table 2 ). No significant differences in safety were identified in patient subgroups by age, gender, race, ethnicity, body mass index, diabetes status, renal impairment, or history of infectious hepatitis B or C [ 7 , 8 , 15–19 ]. Laboratory changes were also similar between delafloxacin-treated patients and the comparator group.…”

Section: Resultsmentioning

confidence: 99%

“…The phase III studies encompass 1510 patients, in which delafloxacin-treated patients received 5–14 days of delafloxacin 300 mg intravenously (IV) and/or 450 mg orally every 12 hours plus a 30-day post-treatment observation period ( Supplementary Table 1) . In these studies, delafloxacin was compared with IV vancomycin 15 mg/kg (actual body weight) plus aztreonam dosed every 12 hours [ 7 , 8 ]. The pooled phase III safety analysis set consisted of 1492 patients who were randomized and received at least 1 dose of the study drug.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Safety of Delafloxacin: Focus on Adverse Events of Special Interest

Lodise

Corey

Hooper

et al. 2018

Open Forum Infectious Diseases

Self Cite

View full text Add to dashboard Cite

BackgroundFluoroquinolones have been widely used for a variety of Gram-positive and Gram-negative infections, and by 2002 they had become the most commonly prescribed class of antibiotics for adults in the United States. With widespread use, the class has become associated with a range of adverse events. Delafloxacin is a fluoroquinolone approved in the United States for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSIs). Delafloxacin is differentiated from other fluoroquinolones due to structural differences and in its activity against methicillin-resistant Staphylococcus aureus, including quinolone-resistant strains. This paper reviews the safety profile of delafloxacin across clinical studies with an emphasis on the incidence of adverse events of special interest that are associated with fluoroquinolones.MethodsData from 2 completed phase III studies of delafloxacin for the treatment of ABSSSIs were pooled and are the primary focus of this paper. Additional support from the full safety analysis set (30 completed phase I to phase III clinical studies) is included where applicable.ResultsFewer patients in the pooled delafloxacin group had AESIs than in the comparator group (7.0% vs 9.2%, respectively). Delafloxacin had a low rate of discontinuations due to treatment-related adverse events (<1%). Serious adverse events occurred at similar rates in patients treated with delafloxacin vs comparators.ConclusionsSerious adverse events occurred at similar rates in patients treated with delafloxacin vs nonquinolone comparators used to treat ABSSSIs.Clinicaltrials.gov identifierNCT01984684 and NCT01811732

show abstract

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Safety of Delafloxacin: Focus on Adverse Events of Special Interest

Lodise

Corey

Hooper

et al. 2018

Open Forum Infectious Diseases

Self Cite

View full text Add to dashboard Cite

show abstract

“…In vitro studies have shown MIC levels for delafloxacin to be 3-5 times lower than other fluoroquinolones against Gram-positive microbes [21]. Additionally, multiple groups have shown its higher in vitro efficacy against Gram-positive organisms compared to other in-class agents [22,23].…”

Section: Discussionmentioning

confidence: 99%

In vitro Susceptibilities of Methicillin-Susceptible and Resistant Staphylococci to Traditional Antibiotics Compared to a Novel Fluoroquinolone

Fan

Lin

Yannuzzi

et al. 2020

J Ophthal Inflamm Infect

View full text Add to dashboard Cite

Background: To assess the in-vitro efficacy of delafloxacin, a new fourth generation fluoroquinolone, against Staphylococcus vitreous isolates from patients with clinically diagnosed endophthalmitis. This is the first investigation of delafloxacin in ocular tissues. Methods: Intravitreal isolates of culture-proven S. aureus and S. epidermidis were identified between 2014 and 2018. Minimum inhibitor concentrations (MIC) were determined using ETEST strips. The antibiotic susceptibilities were tested against a panel of drugs including glycopeptides such as vancomycin, as well as traditional and newer fluoroquinolones (levofloxacin, moxifloxacin, and delafloxacin). Results: Of 45 total isolates identified between 2014 and 2018, 13% (6) were methicillin-resistant S. aureus (MRSA), 9% (4) were methicillin-sensitive S. aureus (MSSA), 53% (24) were methicillin-resistant S. epidermidis (MRSE), and 24% (11) were methicillin-sensitive S. epidermidis (MSSE). Among the fluoroquinolones, resistance rates were 61% for levofloxacin, 50% for moxifloxacin, and 12% for delafloxacin. Inter-class comparisons between delafloxacin and the two other fluoroquinolones demonstrated higher Gram-positive susceptibility to delafloxacin (p < 0.01). MIC90 values were lowest for delafloxacin (1.0 μg/mL) compared to levofloxacin (8.0 μg/mL) and moxifloxacin (8.0 μg/mL). Vancomycin was 100% effective against all isolates with MIC90 value of 0.75 μg/mL. Conclusion: Compared to levofloxacin and moxifloxacin, the newer fluoroquinolone delafloxacin demonstrated the lowest MICs values and lowest rates of resistance for Gram-positive in-vitro S. epidermidis and S. aureus vitreous isolates.

show abstract

“…22 Interestingly, despite the dedicated renal PK studies of both DLX and M/V used the MDRD equation to define renal impairment, exclusions and dose adjustments for renal dysfunction in their phase 2 and 3 trials were based on eCrCL rather than eGFR (Figure 1). [23][24][25][26] Pharmacometricians Given the relatively small number of subjects with renal impairment enrolled across all phases of clinical drug development, analysis of pooled data is necessary to evaluate the effect of renal impairment on drug exposure across the population. Pharmacometricians use population modeling and simulation to perform structured evaluation of covariate effects on drug PK.…”

Section: Implications Across the Medication Use Systemmentioning

confidence: 99%

Estimating Renal Function in Drug Development: Time to Take the Fork in the Road

Crass

Pai

2018

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Renal function is the most commonly applied patient-specific quantitative variable used to determine drug doses. Measurement of renal function is not practical in most clinical settings; therefore, clinicians often rely on estimates when making dosing decisions. Similarly, renal function estimates are used to assign subjects in phase 1 pharmacokinetic studies, which inform dosing in late-phase clinical trials and ultimately the product label. The Cockcroft-Gault estimate of creatinine clearance has been the standard renal function metric; however, this paradigm is shifting toward the Modification of Diet in Renal Diseases (MDRD) estimate of the glomerular filtration rate (GFR). The proportion of approved new drug labels with dosing recommendations based on the MDRD equation was 16.7% in 2015, 70.0% in 2016, and 46.7% in 2017. Disharmonious recommendations from the United States Food and Drug Administration and the European Medicines Agency will continue to increase this heterogeneity in the assessment of renal function in drug development and negatively impact industry, health systems, and clinicians. In this review, we discuss the current regulatory guidance for the conduct of renal impairment pharmacokinetic studies and review the implications of this guidance across the medication use system with 3 recently approved antibiotics: ceftazidime/avibactam, delafloxacin, and meropenem/vaborbactam. Finally, we suggest measuring GFR in phase 1 studies and employing the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to integrate data across clinical trials. This will help to harmonize CKD staging, population pharmacokinetic analyses, and dosing by estimated renal function.

show abstract

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

Abstract: This phase 3 trial in acute bacterial skin and skin structure infections showed IV followed by oral delafloxacin to be noninferior to IV vancomycin/aztreonam combination therapy and well tolerated. Oral delafloxacin appears to maintain the initial response with IV delafloxacin.

Cited by 82 publications

References 24 publications

Safety of Delafloxacin: Focus on Adverse Events of Special Interest

Safety of Delafloxacin: Focus on Adverse Events of Special Interest

In vitro Susceptibilities of Methicillin-Susceptible and Resistant Staphylococci to Traditional Antibiotics Compared to a Novel Fluoroquinolone

Estimating Renal Function in Drug Development: Time to Take the Fork in the Road

Contact Info

Product

Resources

About