Baxdela (Page 6 of 9)

12.4 Microbiology

Mechanism of Action

Delafloxacin belongs to the fluoroquinolone class of antibacterial drugs and is anionic in nature. The antibacterial activity of delafloxacin is due to the inhibition of both bacterial topoisomerase IV and DNA gyrase (topoisomerase II) enzymes which are required for bacterial DNA replication, transcription, repair, and recombination. Delafloxacin exhibits a concentration-dependent bactericidal activity against gram-positive and gram-negative bacteria in vitro.

Resistance

Resistance to fluoroquinolones, including delafloxacin, can occur due to mutations in defined regions of the target bacterial enzymes topoisomerase IV and DNA gyrase referred to as Quinolone-Resistance Determining Regions (QRDRs), or through altered efflux.

Fluoroquinolones, including delafloxacin, have a different chemical structure and mechanism of action relative to other classes of antibacterial compounds (e.g., aminoglycosides, macrolides, β-lactams, glycopeptides, tetracyclines and oxazolidinones).

In vitro resistance to delafloxacin develops by multiple step mutations in the QRDRs of gram-positive and gram-negative bacteria. Delafloxacin-resistant mutants were selected in vitro at a frequency of < 10-9.

Although cross-resistance between delafloxacin and other fluoroquinolone-class antibacterial agents has been observed, some isolates resistant to other fluoroquinolone-class antibacterial agents may be susceptible to BAXDELA including some S. aureus isolates carrying mutations in the quinolone resistance determining region (gyrA, parC and parE).

Additionally, delafloxacin has activity against some isolates of beta-lactamase positive H. influenzae and H. parainfluenzae.

Interaction With Other Antimicrobials

In vitro drug combination studies with delafloxacin and amoxicillin/clavulanate, azithromycin, aztreonam, ceftaroline, ceftazidime, ceftriaxone, colistin, daptomycin, doxycycline, linezolid, meropenem, penicillin, rifampin, tigecycline, trimethoprim/sulfamethoxazole and vancomycin demonstrated neither synergy nor antagonism.

Antimicrobial Activity

BAXDELA has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections, [see Indications and Usage (1.1, 1.2)].

Acute Bacterial Skin and Skin Structure Infections (ABSSSI)

Aerobic bacteria

Gram-positive bacteria
Staphylococcus aureus
(including methicillin-resistant and methicillin-susceptible isolates)
Staphylococcus haemolyticus
Staphylococcus lugdunensis
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus
Group (including S. anginosus , S. intermedius , and S. constellatus)
Enterococcus faecalis
Gram-negative bacteria
Escherichia coli
Klebsiella pneumoniae
Enterobacter cloacae
Pseudomonas aeruginosa

Community-Acquired Bacterial Pneumonia (CABP)

Aerobic bacteria

Gram-positive bacteria
Streptococcus pneumoniae
Staphylococcus aureus
(methicillin-susceptible isolates only)
Gram-negative bacteria
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Pseudomonas aeruginosa
Other microorganisms
Chlamydia pneumoniae
Legionella pneumophila
Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint of delafloxacin against isolates of similar genus or organism group. However, the efficacy of BAXDELA in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Aerobic bacteria

Gram-positive bacteria
Streptococcus dysgalactiae
Gram-negative bacteria
Enterobacter aerogenes
Klebsiella oxytoca
Proteus mirabilis
Moraxella catarrhalis

Susceptibility Test Methods

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have not been conducted with BAXDELA.

Delafloxacin was not mutagenic in a bacterial reverse mutation (Ames) assay, and was not clastogenic in a mouse bone marrow micronucleus test at ≥ 15 times the estimated human plasma exposure based on AUC. In an in vitro clastogenicity assay using isolated human lymphocytes, delafloxacin was negative in short incubations (~3 hours) and, at high cytotoxic concentrations (> 1.0 mM), was positive in a long incubation (~19 hours).

Delafloxacin did not affect the fertility of male and female rats up to the highest intravenous dose tested (120 mg/kg/day); female rats were dosed 2 weeks prior to mating and through gestation day 7 and male rats were treated for 28 days prior to mating and beyond for a total of 58-59 days. AUC in male and female (non-pregnant and pregnant) rats at 120 mg/kg/day delafloxacin intravenous was estimated to be approximately 5 times the estimated human plasma exposure based on AUC in separate intravenous toxicology studies in rats, one of which was a 2-week study that used a different vehicle for delafloxacin than in the fertility study, and another was an 8-day study in nonpregnant and pregnant (gestation day 13) rats that used the same vehicle for delafloxacin as in the fertility study.

13.2 Animal Toxicology and/or Pharmacology

Fluoroquinolone antibacterials are associated with degenerative changes in articular cartilage and arthropathy in skeletally immature animals. In a toxicology study of the formulated tablet in dogs, the femoral head of one of three high dose (480 mg/kg/day) females had minimal focal degeneration of the superficial articular cartilage and a small focal cleft in the articular cartilage. No other joints were examined.

14 CLINICAL STUDIES

14.1 Acute Bacterial Skin and Skin Structure Infections

A total of 1510 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized in 2 multicenter, multinational, double-blind, double-dummy, non-inferiority trials. Trial 1 compared BAXDELA 300 mg via intravenous infusion every 12 hours to comparator. In Trial 2, patients received BAXDELA 300 mg via intravenous infusion every 12 hours for 6 doses then made a mandatory switch to oral BAXDELA 450 mg every 12 hours. In both studies, the comparator was the intravenous combination of vancomycin 15 mg/kg actual body weight and aztreonam. Aztreonam therapy was discontinued if no gram-negative pathogens were identified in the baseline cultures.

In Trial 1, 331 patients with ABSSSI were randomized to BAXDELA and 329 patients were randomized to vancomycin plus aztreonam. Patients in this trial had the following infections: cellulitis (39%), wound infection (35%), major cutaneous abscess (25%), and burn infection (1%). The overall mean surface area of the infected lesion as measured by digital planimetry was 307 cm2. The average age of patients was 46 years (range 18 to 94 years). Patients were predominately male (63%) and white (91%); 32% had BMI ≥ 30 kg/m2. The population studied in Trial 1 included a distribution of patients with associated comorbidities such as hypertension (21%), diabetes (9%), and renal impairment (16%; 0.2% with severe renal impairment or ESRD). Current or recent history of drug abuse, including IV drug abuse, was reported by 55% of patients. Bacteremia was documented at baseline in 2% of patients.

In Trial 2, 423 patients were randomized to BAXDELA and 427 patients were randomized to vancomycin plus aztreonam. Patients in this trial had the following infections: cellulitis (48%), wound infection (26%), major cutaneous abscess (25%), and burn infection (1%). The overall mean surface area of the infected lesion, as measured by digital planimetry, was 353 cm2. The average age of patients was 51 years (range 18 to 93 years). Patients were predominately male (63%) and white (83%); 50 % had a BMI ≥ 30 kg/m2. The population studied in Trial 2 included a distribution of patients with associated comorbidities such as hypertension (31%), diabetes (13%) and renal impairment (16%; 0.2% with severe renal impairment or ESRD). Current or recent history of drug abuse, including IV drug abuse, was reported by 30% of patients. Bacteremia was documented at baseline in 2% of patients.

In both trials, objective clinical response at 48 to 72 hours post initiation of treatment was defined as a 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema. Table 7 summarizes the objective clinical response rates in both of these trials.

Table 7 Clinical Response at 48–72 hours * in the ITT Population with ABSSSI in Trial 1 and Trial 2
CI = Confidence Interval; ITT = Intent To Treat and includes all randomized patients
*
Objective clinical response was defined as a 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema at 48 to 72 hours after initiation of treatment without any reasons for failure (less than 20% reduction in lesion size, administration of rescue antibacterial therapy, use of another antibacterial or surgical procedure to treat for lack of efficacy, or death). Missing patients were treated as failures.
Treatment difference, expressed as percentage, and CI based on Miettinen and Nurminen method without stratification.
Trial BAXDELA(300 mg IV) Vancomycin 15 mg/kg + Aztreonam Treatment Difference (2-sided 95% CI)
Trial 1
Total N 331 329
Responder, n (%) 259 (78.2%) 266 (80.9%) -2.6 (-8.8, 3.6)
BAXDELA (300 mg IV and 450 mg oral) Vancomycin 15 mg/kg + Aztreonam
Trial 2
Total N 423 427
Responder, n (%) 354 (83.7%) 344 (80.6%) 3.1 (-2.0, 8.3)

In both trials, an investigator assessment of response was made at Follow-up (Day 14 ± 1) in the ITT and CE populations. Success was defined as “cure + improved,” where patients had complete or near resolution of signs and symptoms, with no further antibacterial needed. The success rates in the ITT and CE populations are shown in Table 8.

Table 8 Investigator-Assessed Success at the Follow-up Visit in ABSSSI —ITT Population and CE Population in Trial 1 and 2
CI = Confidence Interval; ITT = Intent To Treat and includes all randomized patients; CE = Clinically Evaluable consisted of all ITT patients who had a diagnosis of ABSSSI, received at least 80% of expected doses of study drug, did not have any protocol deviations that would affect the assessment of efficacy and had investigator assessment at the Follow-Up Visit.
*
Treatment difference, expressed as percentage, and CI based on Miettinen and Nurminen method without stratification.
Success was cure + improved where patients had complete or near resolution of signs and symptoms with no further antibacterial needed.
Trial BAXDELA (300 mg IV) Vancomycin 15 mg/kg + Aztreonam Treatment Difference *(2-sided 95% CI)
Trial 1
Success , n/N (%) ITT 270/331 (81.6%) 274/329 (83.3%) -1.7 (-7.6, 4.1)
Success , n/N (%) CE 232/240 (96.7%) 238/244 (97.5%) -0.9 (-4.3, 2.4)
BAXDELA (300 mg IV and 450 mg Oral) Vancomycin 15 mg/kg + Aztreonam
Trial 2
Success, n/N (%) ITT 369/423 (87.2%) 362/427 (84.8%) 2.5 (-2.2, 7.2)
Success, n/N (%) CE 339/353 (96.0%) 319/329 (97.0%) -0.9 (-3.9, 2.0)

Six delafloxacin patients had baseline S. aureus bacteremia with ABSSSI. Five of these 6 patients (83.3%) were clinical responders at 48 to 72 hours and 5/6 (83.3%) were considered clinical success for ABSSSI at Day 14 ± 1. Two delafloxacin patients had baseline Gram-negative bacteremia (K. pneumoniae and P. aeruginosa), and both were clinical responders and successes.

The investigator assessments of clinical success rates were also similar between treatment groups at Late Follow-up (LFU, day 21-28).

Objective clinical response and investigator-assessed success by baseline pathogens from the primary infection site or blood cultures for the microbiological ITT (MITT) patient population pooled across Trial 1 and Trial 2 are presented in Table 9.

Table 9 Outcomes by Baseline Pathogen (Pooled across Trial 1 and Trial 2; MITT * Population)
Clinical Response at 48–72 hours Investigator-Assessed Success at Follow-up
BAXDELA Comparator BAXDELA Comparator
Pathogen n/N (%) n/N (%) n/N (%) n/N (%)
*
Microbiological ITT (MITT) consists of all randomized patients who had a baseline pathogen identified that is known to cause ABSSSI.
Objective clinical response was defined as a 20% or greater decrease in lesion size as determined by digital planimetry of the leading edge of erythema at 48 to 72 hours after initiation of treatment.
Investigator-assessed success was defined as complete or near resolution of signs and symptoms, with no further antibacterial needed at Follow-up Visit (Day14 ± 1).
§
Discrepancy in the total numbers is due to the multiple subjects having both MRSA and MSSA isolates.
Staphylococcus aureus 271/319 (85.0) 269/324 (83.0) 275/319 (86.2) 269/324 (83.0)
Methicillin-susceptible § 149/177 (84.2) 148/183 (80.9) 154/177 (87.0) 153/183 (83.6)
Methicillin-resistant § 125/144 (86.8) 121/141 (85.8) 122/144 (84.7) 116/141 (82.3)
Streptococcus pyogenes 17/23 (73.9) 9/18 (50.0) 21/23 (91.3) 16/18 (88.9)
Staphylococcus haemolyticus 11/15 (73.3) 7/8 (87.5) 13/15 (86.7) 7/8 (87.5)
Streptococcus agalactiae 10/14 (71.4) 9/12 (75.0) 12/14 (85.7) 11/12 (91.7)
Streptococcus anginosus Group 59/64 (92.2) 55/61 (90.2) 54/64 (84.4) 47/61 (77.0)
Staphylococcus lugdunensis 8/11 (72.7) 6/9 (66.7) 10/11 (90.9) 8/9 (88.9)
Enterococcus faecalis 11/11 (100.0) 12/16 (75.0) 9/11 (81.8) 14/16 (87.5)
Escherichia coli 12/14 (85.7) 16/20 (80.0) 12/14 (85.7) 18/20 (90.0)
Enterobacter cloacae 10/14 (71.4) 8/11 (72.7) 12/14 (85.7) 10/11 (90.9)
Klebsiella pneumoniae 19/22 (86.4) 22/23 (95.7) 20/22 (90.9) 21/23 (91.3)
Pseudomonas aeruginosa 9/11 (81.8) 11/12 (91.7) 11/11 (100.0) 12/12 (100.0)

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.