Iclaprim Shows Consistent, Potent Activity Against Beta-Hemolytic Streptococci

Investigators find iclaprim to be active against a worldwide collection of drug-susceptible and drug-resistant beta-hemolytic streptococci from patients with skin and skin structure infections.

Surveillance data collected before 2006 has shown that MotifBio’s iclaprim is active against beta-hemolytic pathogens, including pathogens that have developed resistance to available antibiotics.

Now, in a new study, investigators found that iclaprim demonstrated potent in vitro activity against drug-susceptible and drug-resistant beta-hemolytic streptococci collected from patients with skin and skin structure infections between 2012 and 2016.

The results were presented at the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)/American Society for Microbiology (ASM) Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance, which took place in Lisbon, Portugal, September 4-7, 2018.

Iclaprim is a diaminopyrimidine antibiotic that inhibits an essential bacterial enzyme referred to as dihydrofolate reductase (DHFR), which plays a critical role in the bacterial folate synthesis pathway. The treatment works in a way that differs from most antibiotics that are currently on the market in that it is able to quickly kill bacteria in vitro.

“It has a very unique mechanism of action where, in the future—and we can’t say conclusively, but it will look very difficult because of its 2 mechanisms—for resistance to occur,” William O’ Riordan, MD, FACP, chief medical officer of eStudySite, told Contagion® in a past interview. “I think it is unique feature of this antibiotic. It interferes with dihydrofolate reductase, which is intimately involved with the bacterial cell and the cell integrity and does away with the cell itself.”

For the study, investigators tested iclaprim and other antibiotics against isolates of drug-susceptible and -resistant beta-hemolytic streptococci collected from patients with skin and skin structure worldwide from 2012 to 2016.

To do this, the investigators performed antibacterial susceptibility testing by broth microdilution in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines on a total of 458 non-duplicative, non-consecutive isolates—257 were Streptococcus pyogenes and 201 were Streptococcus agalactiae. The isolates were collected from several regions across the globe, including Europe (n=205), North America (204), Latin America (26), and Asia Pacific (23).

The investigators used CLSI breakpoints to interpret minimum inhibitory concentrations (MIC): erythromycin (S ≤0.25, R ≥ 1 µg/mL), azithromycin (S ≤0.5, R ≥2 µg/mL), and tetracycline (S ≤2, R ≥8 µg/mL).

Iclaprim demonstrated consistent and potent activity against S pyogenes in isolates that were susceptible or resistant to erythromycin and azithromycin. Furthermore, investigators noted that MIC50 and MIC90 (µg/mL) values were higher for iclaprim in isolates that were tetracycline-resistant S pyogenes compared with tetracycline-susceptible isolates.

Iclaprim also proved to have consistent and potent activity against S agalactiae. The investigators report that MIC50 and MIC90 (µg/mL) values against drug-susceptible isolates were either identical or within 2-fold of those observed against erythromycin, azithromycin, and tetracycline-resistant isolates.

As such, the authors conclude that iclaprim demonstrated activity against a worldwide collection of drug-susceptible and -resistant beta-hemolytic streptococci collected from patients with skin and skin structure infections. With bacteria becoming increasingly resistant to available antibiotics, the need for more treatments with a low propensity for resistance development—such as iclaprim—are imperative.

“Continued surveillance is warranted to monitor the activity of iclaprim against beta-hemolytic streptococci,” the authors write, “as well as to detect any potential emergence of resistance.”

The US Food and Drug Administration accepted a New Drug Application and granted Priority Review for iclaprim in August for the treatment of acute bacterial skin and skin structure infections.

The approval was based on promising results yielded from 2 phase 3 trials—REVIVE-1 and REVIVE-2—which established the safety and effectiveness of the drug compared with vancomycin, the standard of care.