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

BACKGROUND – THE STUDY QUESTION?

Background  Skin and soft tissue infections are among the most common infections seen in the hospital
setting and historically, gram-positive pathogens are the most common. However, gram-
negative pathogens can also cause infection and are associated with a longer length of stay,
greater mortality and higher total costs.
 Delafloxacin is a novel anionic fluoroquinolone with activity against gram-positive, gram-
negative, atypical, and anaerobic organisms. Specifically, delafloxacin includes coverage of
MRSA and Pseudomonas.
 Delafloxacin demonstrates excellent in vitro activity against gram-positive pathogens compared
to other fluoroquinolones, while also retaining good coverage against gram-negative organisms.
 Due to its unique bacterial coverage and oral formulation availability, delafloxacin is a potential
option for patients with acute bacterial skin and skin structure infections (ABSSSIs).
Previous trials
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
Why this study? Is IV followed by oral delafloxacin efficacious and safe for treatment of ABSSSI compared with
vancomycin plus aztreonam
GENERAL STUDY OVERVIEW
Title/Citation 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
Funding  Funded by Melinta Therapeutics
Null Hypothesis  Intravenous followed by oral delafloxacin is inferior compared to vancomycin plus aztreonam
for the treatment of acute bacterial skin and skin structure infections in reducing lesion size at
48-72 hours.
Trial design  Multicenter, randomized, double-blind trial
Objectives  Approval of IV and oral delafloxacin for ABSSSI
Enrollment  Patients at 76 study centers in 16 countries between May 2014 and January 2016.
 Patients were randomized by infection category and baseline BMI. Infection categories were
limited to ≤25% of patients with a major cutaneous abscess and ≤30% with wound infections.
Patients were characterized by BMI <30 kg/m2 and ≥30 kg/m2.
METHODS (only list pertinent trial info in this section: refer to trial for further details)
Inclusion criteria  ≥18 years of age
 Diagnosis of ABSSSI of at least 1 of the following 4 types: cellulitis/erysipelas, wound
infection, major cutaneous abscess or burn infection.
1. Patients had to have at least 2 of the following signs of systemic infection:
 Lymph node enlargement due to the present infection
 Documented fever ≥ 38°C (100.4°F) taken orally (or the equivalent value for the
temperature recording method used)
 Lymphangitis
 Elevated white blood cells (WBCs) of ≥ 10,000 cells/µL in the 48 hours prior to first
dose of study drug
 Elevated C-reactive protein (CRP) (> 10 × upper limit of normal [ULN]) in the
48 hours prior to first dose of study drug
 Purulent or seropurulent drainage or discharge
 Suitable candidate for IV antibiotic therapy
 Sexually active women and men with partners of childbearing potential had to agree to use an
acceptable form of contraception, as determined by the investigator
Exclusion criteria 1. Medical history of significant hypersensitivity or allergic reaction to quinolones,
beta-lactams, vancomycin, or vancomycin derivatives according to the judgment of the
investigator.

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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

2. Women who were pregnant or lactating.

3. Any chronic or underlying skin condition at the site of infection that may have complicated
the assessment of response (e.g., atopic dermatitis or eczema). Any other skin condition
that, in the opinion of the investigator, would have interfered with objective measurement
of the ABSSSI under treatment.
4. Infection associated with a prosthetic joint or the removal of a prosthetic joint, or infection
involving other prosthetic materials or foreign bodies (e.g., catheter tunnels) unless that
other prosthetic material was removed within 24 hours after starting study drug.
5. Infection associated with any of the following:
Human or animal bite (insect bites were not considered animal bites)
Osteomyelitis
Decubitus ulcer
Diabetic foot ulcer
Septic arthritis
Mediastinitis
Sternal wound
Necrotizing fasciitis, anaerobic cellulitis, or synergistic necrotizing cellulitis
Myositis
Tendinitis
Endocarditis
Toxic shock syndrome
Sustained shock (blood pressure < 90 mmHg for > 2 hours despite adequate fluid
resuscitation, with evidence of hypoperfusion or use of sympathomimetic agents to
maintain blood pressure)
Gangrene or gas gangrene
Burns covering  10% of body surface area
Severely impaired arterial blood supply to an extremity with an ABSSSI (a patient with
a palpable distal pulse or an audible distal pulse by Doppler could have been enrolled)
Current evidence of deep vein thrombosis or superficial thrombophlebitis
Any infection types with poor circulatory status in the opinion of the investigator
6. Minor abscesses, unless present with 1 of the 4 acceptable types of ABSSSIs noted in
inclusion criteria.
7. Any infection expected to require other systemic antibacterial agents in addition to study
drug.
8. Receipt of systemic antibiotic therapy in the 14 days before enrollment unless 1 of the
following was documented:
The patient received at least 48 hours of antibiotic therapy for ABSSSI AND the clinic
notes or photographs document the clinical progression of ABSSSI (i.e., not by patient
history alone).
The patient recently (within 14 days) completed a treatment course with an
antibacterial drug for an infection other than ABSSSI and the drug does not have
activity against bacterial pathogens that cause ABSSSI.
The patient received only 1 dose of either a single, potentially effective, short-acting
(dosed every 12 hours or more frequently) antimicrobial drug or a short-acting (dosed
every 12 hours or more frequently) antimicrobial drug regimen for treatment of the
ABSSSI under study before enrollment (Note: 1 dose of a regimen was defined as the
standard therapy for ABSSSI at the study site).
Patients who received 1 dose of either a single, potentially effective, short-acting
antimicrobial drug or regimen for treatment of the ABSSSI under study in the
14 days before study entry were limited to no more than 25% of total randomized
patients.

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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

9. Anticipated to require either an amputation or multiple debridement procedures.

10. Anticipated that the ABSSSI under treatment required more than 28 doses of antibiotic
therapy.
11. Severely compromised immune systems, for example:
Known absolute neutropenia (absolute neutrophil count < 500 cells/µL)
Known human immunodeficiency virus infection with a CD4 count < 350 cells/µL
within the last 4 months
Cancer chemotherapy or radiation in the last 3 months
During the period starting from 14 days before study drug administration through the
Follow-up Visit, the anticipated cumulative use of systemic corticosteroids
was > 10 days and the anticipated corticosteroid dose was equivalent to > 15 mg of
prednisone per day.
12. Known history of Child-Pugh Class B or C liver disease.
13. Alanine aminotransferase > 3 × ULN.
14. Patients with end-stage renal disease on hemodialysis or peritoneal dialysis or CrCl
of < 15 mL/min using the Cockcroft-Gault formula.
15. Patients with ongoing treatment for seizures or untreated history of seizures.
16. Life expectancy of < 3 months.
17. Immediate life-threatening disease.
18. Any underlying disease (e.g., severe cardiac disease, malignancy, or psychiatric disorder)
that, in the opinion of the investigator, could have interfered with the patient’s ability to
participate in the study.
19. Prior treatment with delafloxacin within the last year.
20. Receipt of an investigational drug within 30 days of randomization.
21. Prior randomization into this study.
22. Body weight > 200 kg.
23. Required a total infusion time for vancomycin of > 3 hours per dose (e.g., > 3000 mg per
3-hour dose).
24. History or physical examination finding of peripheral neuropathy.
Interventions  Delafloxacin 300 mg IV q12h for 3 days with a switch to 450 mg PO BID
 Vancomycin 15 mg/kg IV with aztreonam 1g q12h IV, with aztreonam being discontinued if no
gram-negative microorganisms are present in baseline cultures at 48 hours
Endpoints  FDA Primary outcome: Objective response assessment 48-72 hours after initiation of treatment
based on ≥20% decrease in lesion size assessed by digital planimetry of the leading edge in the
absence of clinical failure.
The definition of clinical failure was (1) <20% reduction of the ABSSSI lesion spread of erythema
area; (2) administration of rescue antibacterial drug therapy or administration of nonstudy
antibacterial drug therapy for treatment of the ABSSSI before the primary efficacy endpoint
assessment; (3) unplanned surgical intervention excluding limited bedside debridement and standard
wound care before the primary efficacy endpoint assessment; or (4) death within 72 hours after
initiation of study drug.
 European Medicines Agency primary outcome: Investigator assessment of clinical response at
the FU visit in the intent to treat population. Categorized as cure, improved, failure, or
indeterminate.

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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

 Secondary outcome: investigator-assessed success (cure plus improved and no further antibiotic
needed) at FU visit.
 Microbiological assessments
 Safety and tolerability assessments
Statistical analyses  Intent to treat analysis
 2-sided 95% CI for noninferiority testing was computed. Noninferiority was concluded in the
lower limit of the 2-sided 95% CI exceeded -10%
 Descriptive statistics described continuous variables while counts and percentages were
calculated for categorical data
RESULTS
Monitoring  Telephone follow-up was conducted 30 days following the last dose of study drug
Enrollment 

Baseline characteristics

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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

96% of MRSA isolates were susceptible to delafloxacin. 20.7% of pathogens were gram-
negative.
Endpoints Clinically evaluable (CE) analysis set included all patients in the ITT population who (1) received
≥80% of the total expected doses of the assigned study drug or experienced clinical failure and
received ≥4 doses of study drug; (2) did not receive any concomitant, systemic antibacterial therapy
with activity against the identified pathogen; and (3) had no major protocol deviations.
In patients with bacteremia, 8/11 delafloxacin-treated patients and 5/8 vancomycin/aztreonam-
treated patients had successful outcomes.

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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

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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

AUTHORS’ CONCLUSIONS

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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

In ABSSSI patients, IV/oral delafloxacin monotherapy was noninferior to IV vancomycin + aztreonam

combination therapy for both the objective response and the investigator-assessed response at follow-up and
late follow-up. Delafloxacin was well tolerated as monotherapy in treatment of ABSSSIs.

GENERALIZABILITY/CRITIQUE/DISCUSSION
Baseline characteristics overall well balanced between two populations
Patient Population 
 Stratification by infection type results were not included
 Exclusion criteria could limit external validity of study
Aztreonam was used with vancomycin
Intervention 
 Vancomycin infusion time could induce bias
 Information about supportive therapy was not included
Potential bias in primary and secondary outcomes
Endpoints 
 Demonstrated efficacy and safety
 Did not assess rates of reinfection
 Unclear the type of cultures obtained
No goal sample size
Statistics 
 ITT, Clinically evaluable analysis set and MRSA infections set was helpful
 P-values were not given

Leader’s Conclusion

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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

ABSSSI classification:
 Cellulitis/erysipelas: A diffuse skin infection characterized by spreading areas of redness of a
minimum surface area of 75 cm2 as determined by measurement of the longest head-to-toe length
(the longest dimension of the infection) multiplied by the longest perpendicular width using a
disposable ruler.
 Wound infection: An infection characterized by purulent drainage from a traumatic or surgical
wound with surrounding redness of a minimum surface area of 75 cm2 (e.g., the shortest distance of
redness extending at least 5 cm from the peripheral margin of the wound) as determined by
measurement of the longest head-to-toe length (the longest dimension of the infection) multiplied by
the longest perpendicular width using a disposable ruler.
 Major cutaneous abscess: An infection characterized by a collection of pus within the dermis or
deeper that was accompanied by redness of a minimum surface area of 75 cm2 (e.g., the shortest
distance of redness extending at least 5 cm from the peripheral margin of the abscess) as determined
by measurement of the longest head-to-toe length (the longest dimension of the infection) multiplied
by the longest perpendicular width using a disposable ruler.
 Burn infection: An infection characterized by purulent drainage that was accompanied by redness of
a minimum surface area of 75 cm2 (e.g., the shortest distance of redness extending at least 5 cm
from the peripheral margin of the burn infection) as determined by measurement of the longest
head-to-toe length (the longest dimension of the infection) multiplied by the longest perpendicular
width using a disposable ruler. Patients with burn infections were only enrolled if the area of the
burn comprised ≤ 10% of the patient’s body surface as determined by the investigator.

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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

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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

Delafloxacin
Drug class: anionic (non-zwitterionic) fluoroquinolone with enhanced potency at acidic pH relative to other fluoroquinolones.
Spectrum of activity:
Gram-positive organisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA]
isolates), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus group
(including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes,
and Enterococcus faecalis, Streptococcus pneumoniae
Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
Haemophilus influenzae, Haemophilus parainfluenzae, Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma
pneumoniae.
Mechanism of action: inhibits DNA gyrase and topoisomerase IV enzymes
Delafloxacin dosing: 450 mg PO q12h or 300 mg IV q12h
Labeled indication: Treatment of acute bacterial skin and skin structure infections caused by susceptible isolates of S. aureus,
staphylococcus haemolyticus, staphylococcus lugduenesis, streptococcus agalactiae, streptococcus anginosus, streptococcus
pyogenes, enterococcus faecalis, e. coli, Enterobacter cloacae, k. pneumoniae, and p. aeruginosa.
BBW: tendinopathy and tendon rupture, peripheral neuropathy and CNS effects. Avoid in patients with myasthenia gravis.
Administration: Oral: administer at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, sucralfate,
metal cations, or multivitamins containing zinc or iron
Adverse events: headache, nausea, diarrhea, C diff infection, increased serum transaminases.
Warnings: Aortic aneurysm and dissection, glucose regulation, superinfection.
IV formulation contains cyclodextrin
Half-life: IV 3.7 hours (single dose), oral 4.2-8.5 hours (multiple dose)

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