By Lina Meng, PharmD, BCPS, BCCCP

Stanford Antimicrobial Safety and Sustainability Program, Stanford Health Care

Dr. Meng reports no financial relationships relevant to this field of study.

Delafloxacin is a new broad-spectrum fluoroquinolone with in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative organisms including Pseudomonas aeruginosa, and fluoroquinolone-resistant Klebsiella pneumoniae, atypical organisms, and anaerobes including Bacteroides fragilis. It is available both intravenously and orally. Delafloxacin was approved by the U.S. Food and Drug Administration in June 2017 for Acute Bacterial Skin and Skin Structure Infections (ABSSSI), based on two global Phase III trials for ABSSSI showing non-inferiority to vancomycin plus aztreonam for the primary endpoint of clinical response at 48-72 hours.1,2 In a post-hoc analysis of these studies, delafloxacin achieved high microbiological response rates against levofloxacin-non-susceptible S. aureus isolates (80/81; 98.8%) and MRSA isolates (70/71; 98.6%).3

Structural modifications to delafloxacin improve its basicity, which is theorized to improve transmembrane passage and its activity in acidic environments. Delafloxacin may have a role in infections involving biofilms and low pH based on in vitro studies, but whether this translates into benefit in the clinical setting remains to be seen.4

In vitro studies suggest a low probability of selection of resistant mutants: Spontaneous resistance was seen in 2 × 10-9 to < 9.5 × 10-11 in MRSA strains.5 Delafloxacin’s activity against Gram-positive organisms may be enhanced by its inhibition of DNA gyrase (topoisomerase II) and topoisomerase IV enzymes to similar degrees, which is unlike other fluoroquinolones that have a greater affinity for topoisomerase IV in Gram-positive organisms.5 Additionally, efflux pumps did not affect delafloxacin activity in vitro.5

A survey of isolates collected at U.S. and European medical centers in 2014 found that U.S. isolates of MRSA exhibited delafloxacin MIC50 values over 64 times lower than levofloxacin and ciprofloxacin MIC50 values. (See Table 1.) Delafloxacin was the most active fluoroquinolone against S. pneumoniae and S. viridans group streptococci, showing MIC90 values over 64 times lower than levofloxacin. Against P. aeruginosa, delafloxacin and ciprofloxacin were two-fold more active against levofloxacin. (See Table 1.) In a separate study, delafloxacin and ciprofloxacin exhibited MIC50/90 values of 32/128 µg/mL for levofloxacin-resistant P. aeruginosa.4

Table 1. Activities of Delafloxacin and Comparator Fluoroquinolones (U.S. Isolates, 2014 survey)6

Organism group

% of isolates susceptible by CLSI criteria

MIC50 (µg/mL)

MIC90 (µg/mL)

Notes

MRSA

Delafloxacin

-

0.06

0.5

87.6% of isolates susceptible at MIC ≤ 0.25 µg/mL, the manufacturer’s proposed breakpoint for susceptible7

Levofloxacin

30%

4

> 4

 

Ciprofloxacin

0%

> 128

> 128

 

S. pneumoniae

Delafloxacin

-

0.008

0.015

 

Levofloxacin

98.9%

1

1

 

P. aeruginosa

Delafloxacin

-

0.25

> 4

65% of isolates susceptible at MIC ≤ 0.5 µg/mL, the manufacturer’s proposed breakpoint for susceptible7

Levofloxacin

72.5%

0.5

> 4

 

Ciprofloxacin

75.0%

0.25

> 4

 

ADVERSE EFFECTS/WARNINGS7

Delafloxacin carries similar black box warnings as other fluoroquinolones for tendinitis and tendon rupture, peripheral neuropathy, central nervous system effects, and exacerbation of myasthenia gravis. Other notable adverse effects include hypersensitivity reactions and Clostridium difficile-associated diarrhea.

Its effects on QTc were studied in healthy adults at doses up to 900 mg.9 Changes in QTc interval, corrected for heart rate using Fridericia’s formula, were less than 10 milliseconds compared to baseline.

DRUG INTERACTIONS7

Delafloxacin should be taken at least two hours before or six hours after antacids or multivitamins containing aluminum, magnesium, sucralfate, zinc, or iron due to interference with delafloxacin’s absorption.

CONCLUSIONS

Delafloxacin is an orally available alternative in ABSSSI when MRSA (including fluoroquinolone-resistant strains) might be involved. Its activity against fluoroquinolone-resistant S. pneumoniae, K. pneumoniae, and E. coli is of interest. However, use in monomicrobial infections likely would result in employment of an antibiotic with an unnecessarily broad spectrum. With in vitro activity against B. fragilis, delafloxacin may prove useful in mixed aerobic-anaerobic infections, or mixed S. aureus and P. aeruginosa infections. Its potential role in other infections where highly bioavailable oral options are needed (such as osteomyelitis or bacteremia) would need to be validated first in clinical studies. Additionally, although in vitro delafloxacin resistance to MRSA was infrequent, there is a general concern of selective pressure and the emergence of quinolone resistance, particularly in S. aureus.

Table 2. Dosing in Adults With ABSSSI7

Renal function (mL/min/1.73 m2)

Dosing

As calculated using the Modification of Diet in Renal
Disease (MDRD) eGFR equation

eGFR ≥ 30

450 mg PO q12h for 5-14 days

300 mg IV q12h for 5-14 days

300 mg IV q12h, then switch to
450 mg PO q12h for a total duration
of 5 to 14 days

eGFR < 30

PO: No dosage adjustment necessary

IV: 200 mg IV q12h ± switch to 450 mg PO q12h

eGFR < 15 or ESRD on hemodialysis

Use is not recommended; contains cyclodextrin

Table 3. Pharmacokinetics/Pharmacodynamics7,8

Absorption

• PO bioavailability (450 mg tablet) 58.8%

• Time to peak: 1 hour

Distribution

Vd,ss: 30-48 L (approximates total body water)

 

Plasma protein binding 84%
(primarily to albumin)

Metabolism

• Unchanged parent drug is predominant component in plasma

• Glucuronidation (UGT1A1, UGT1A3, and UGT2B15) accounts for ~1% of administered dose

Elimination

Renal CL: 35-45% of total clearance

 

t1/2 (h): 3.7 ± 0.7 (single IV dose);
4.2-8.5 h (multiple dose PO)

Excretion

• IV: 65% unchanged (urine), 28% unchanged (feces)

• PO: 50% unchanged (urine), 48% unchanged (feces)

Pharmacodynamic target

AUC/MIC

REFERENCES

  1. ClinicalTrials.gov. Delafloxacin versus vancomycin and aztreonam for the treatment of acute bacterial skin and skin structure infections. Melinta Therapeutics, Inc. Available at: https://clinicaltrials.gov/ct2/show/NCT01811732. NML Identifier: NCT01811732. Accessed Sept. 8, 2017.
  2. ClinicalTrials.gov. Delafloxacin vs vancomycin and aztreonam for the treatment of acute bacterial skin and skin structure infections. Melinta Therapeutics, Inc. Available at: https://clinicaltrials.gov/ct2/show/NCT01984684. NML Identifier: NCT01984684. Accessed Sept. 8, 2017.
  3. McCurdy S, Lawrence L, Quintas M, et al. 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 2017;61:pii:e00772-17.
  4. Candel FJ, Penuelas M. Delafloxacin: Design, development and potential place in therapy. Drug Des Devel Ther 2017;11:881-891.
  5. Remy JM, Tow-Keogh CA, McConnell TS, et al. Activity of delafloxacin against methicillin-resistant Staphylococcus aureus: Resistance selection and characterization. J Antimicrob Chemother 2012;67:2814-2820.
  6. Pfaller MA, Sader HS, Rhomberg PR, Flamm RK. In vitro activity of delafloxacin against contemporary bacterial pathogens from the United States and Europe, 2014. Antimicrob Agents Chemother 2017;61:ppii: e02609-16.
  7. Melinta Therapeutics, Inc. BAXDELA Prescribing Information. Available at: www.melinta.com. Accessed Sept. 8, 2017.
  8. Lepak AJ, Andes DR. In vivo pharmacodynamic target assessment of delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in a murine lung infection model. Antimicrob Agents Chemother 2016;60:4764-4769.
  9. Litwin JS, Benedict MS, Thorn MD, 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.