Iclaprim: a differentiated option for the treatment of skin and skin structure infections

ABSTRACT

Introduction: Iclaprim is a selective bacterial dihydrofolate reductase (DHFR) inhibitor. Although there are alternative options for the treatment of acute bacterial skin and skin structure infections (ABSSSI), iclaprim is differentiated from other available antibiotics.

Areas covered: Iclaprim is under clinical development for ABSSSI. This review summarizes the mechanism of action, pharmacokinetics, microbiology, clinical development program, and the differentiation of iclaprim from other antibiotics.

Expert commentary: Iclaprim has a different mechanism of action (DHFR inhibitor) compared to most other antibiotics, is active and rapidly bactericidal against Gram-positive pathogens including antibiotic-resistant pathogens, and suppresses bacterial exotoxins (alpha hemolysin, Panton Valentine leukocidin, and toxic shock syndrome toxin-1). Compared to trimethoprim, iclaprim has lower MIC_90s, can be given without a sulfonamide, overcomes select trimethoprim resistance, and does not cause hyperkalemia. Iclaprim is administered as a fixed dose, does not require dose adjustment in renally-impaired or obese patients, and was not associated with nephrotoxicity in the Phase 3 pivotal REVIVE studies. Iclaprim represents a novel, alternative option for the treatment of severe skin and skin structure infections due to Gram-positive bacteria, particularly in patients at risk of acute kidney injury.

KEYWORDS:

• Iclaprim
• acute bacterial skin and skin structure infection
• methicillin-resistant Staphylococcus aureus
• antibiotic-resistant bacteria
• exotoxins
• renal impairment

Acknowledgments

The authors thank the participants, investigators and research staff for their support of iclaprim clinical trials.

Declarations of interest

S Noviello and D Huang are employees of Motif BioSciences. G. Ralph Corey has received consultancy fees from Cempra Pharmaceuticals, PRA International, Furiex Pharmaceuticals, Inimex Pharmaceuticals, Dr. Reddy’s Laboratories, Cubist Pharmaceuticals, Cerexa/Forest Laboratories, AstraZeneca, GlaxoSmithKline, Pfizer, Merck, Trius Therapeutics, ContraFect, Theravance, and Astellas Pharma and served on an advisory board for Pfizer, Polymedix, Trius Therapeutics, Rib-x . Pharmaceuticals, Seachaid Pharmaceuticals, BioCryst Pharmaceuticals, Durata Therapeutics, Achaogen, Gilead Sciences, ContraFect, Cempra, and Nabriva Therapeutics as well as receiving research grants from Theravance, Innocoll, and The Medicines Company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on the manuscript disclosed receipt of a small research grant from GSK in 2017 and served as a paid consultant for Baxter in 2018.

Additional information

Funding

This manuscript was supported by Motif BioSciences Inc., New York, USA.