Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age

Hoover, Randall; Hunt, Thomas L.; Benedict, Michael; Paulson, Susan K.; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

doi:10.1016/j.clinthera.2015.10.016

Cited by 47 publications

(64 citation statements)

References 15 publications

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“…and intravenous (i.v.) formulations have been developed with promising pharmacokinetic (PK) and efficacy results (1,2). Delafloxacin has a broad spectrum of activity that includes drug-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae (3)(4)(5)(6)(7).…”

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confidence: 99%

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

Lepak

Andes

2016

Antimicrob Agents Chemother

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cDelafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the pharmacokinetic/pharmacodynamic (PK/PD) targets in the murine lung infection model for Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae. Four isolates of each species were utilized for in vivo studies: for S. aureus, one methicillin-susceptible and three methicillin-resistant isolates; S. pneumoniae, two penicillinsusceptible and two penicillin-resistant isolates; K. pneumoniae, one wild-type and three extended-spectrum beta-lactamaseproducing isolates. MICs were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies, and drug dosing was by the subcutaneous route. Single-dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40, and 160 mg/kg. For in vivo studies, 4-fold-increasing doses of delafloxacin (range, 0.03 to 160 mg/kg) were administered every 6 h (q6h) to infected mice. formulations have been developed with promising pharmacokinetic (PK) and efficacy results (1, 2). Delafloxacin has a broad spectrum of activity that includes drug-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae (3-7). Previous clinical studies in patients with acute bacterial skin and skin structure infections (ABSSIs) have demonstrated potency and efficacy, especially with respect to S. aureus (8,9).Pneumonia is one of the most common infectious diseases encountered worldwide and remains a significant cause of morbidity and mortality (10). The major pathogen of community-acquired pneumonia (CAP) continues to be S. pneumoniae despite major advances in vaccination development and administration to at-risk populations. In the hospital setting, S. aureus and Gram-negative bacteria are more commonly encountered and are frequently drug resistant (11).Staphylococcus aureus is particularly challenging due to its inherent pathogenicity and increased prevalence of drug-resistant phenotypes (i.e., methicillin-resistant S. aureus [MRSA]) contributing to serious infections. It is the leading bacterial cause of life-threatening infection due to these attributes (12)(13)(14). For example, in the United States, S. aureus is the most common cause of nosocomial infection and leads to more than 80,000 illnesses and 11,000 deaths yearly (12). Unfortunately, there is a paucity of novel agents to treat MRSA pulmonary infections and even fewer that have oral and i.v. formulation options.The objectives of our experiments were to characterize the in vivo efficacy of delafloxacin using a neutropenic murine lung infection model for three common respiratory tract pathogen groups, including S. aureus, S. pneumoniae, and K. pneumoniae. Specifically, the pharmacokinetic/pharmacodynamic (PK/PD) targets of delafloxacin were examined to provide a framework for

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confidence: 99%

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

Lepak

Andes

2016

Antimicrob Agents Chemother

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“…84 Two additional studies examined delafloxacin administered orally. 85 Delafloxacin's terminal half life is about 12 hours when administered intravenously and six to eight hours when administered orally; however, in the latter studies, the half life lengthened after multiple oral doses. Steady state is expected to be achieved by day three.…”

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confidence: 99%

Advances in the medical management of skin and soft tissue infections

McClain

Bohan

Stevens

2016

BMJ

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Skin and soft tissue infections are some of the most common infectious disease diagnoses in both inpatient and outpatient settings. With bacterial resistance to antimicrobials growing, decision making on empiric antibiotics is becoming increasingly difficult. Additionally, the most recent guidance from a professional society on the treatment of skin and soft tissue infections was published in 2014 by the Infectious Diseases Society of America and is now two years old. New antimicrobial agents have been developed and approved for the treatment of skin and soft tissue infections since then, and more are in the pipeline. This review summarizes the evidence on treatments that are new or in development and the potential repurposing of old antimicrobials. The clinical utility of these treatments is also discussed.

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“…There are several studies with DLX, dedicated to pharmacokinetic properties, tolerability, effect of concomitant food administration and safety 35,36. After endovenous administration,35 the value of maximum concentration (C max ) increases proportionally with increasing doses within the range from 300 to 1,200 mg.…”

Section: Introductionmentioning

confidence: 99%

“…The oral bioavailability is 58.8%, with 450 mg taken orally being equivalent to IV infusion of 300 mg for 1 h, permitting oral sequencing 36. Similarly, the C max and AUC increase in the dose was proportional or higher.…”

Section: Introductionmentioning

confidence: 99%

Delafloxacin: design, development and potential place in therapy

Candel¹,

Peñuelas²

2017

DDDT

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Delafloxacin (DLX) is a new fluoroquinolone pending approval, which has shown a good in vitro and in vivo activity against major pathogens associated with skin and soft tissue infections and community-acquired respiratory tract infections. DLX also shows good activity against a broad spectrum of microorganisms, including those resistant to other fluoroquinolones, as methicillin-resistant Staphylococcus aureus. Its pharmacokinetic properties and excellent activity in acidic environments make DLX an alternative in the treatment of these and other infections. In this manuscript, a detailed analysis of this new fluoroquinolone is performed, from its chemical structure to its in vivo activity in recently published clinical trials. Its possible place in the current antimicrobial outlook and in other infectious models is also discussed.

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Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age

Abstract: Delafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (≥1200 mg).

Cited by 47 publications

References 15 publications

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

In Vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a Murine Lung Infection Model

Advances in the medical management of skin and soft tissue infections

Delafloxacin: design, development and potential place in therapy

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