Iclaprim Proves Effective for ABSSSIs in Patients with Diabetes With Fewer Adverse Effects

Patients with diabetes who were treated for acute bacterial skin and skin structure infections (ABSSSIs) with iclaprim had fewer adverse events (AEs) than those who were treated with vancomycin, according to the results of a recent study.

Updated 9/20/2018 at 10:58 AM EST.

Patients with diabetes who were treated for acute bacterial skin and skin structure infections (ABSSSIs) with iclaprim had fewer adverse events (AEs) than patients with diabetes who were treated with vancomycin, according to the results of a recent study 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 with took place in Lisbon, Portugal, September 4-7, 2018.

“Diabetics are running out of many options when it comes to antibiotics treating ABSSSIs,” corresponding author, David B. Huang, MD, PhD, Chief Medical Officer at Motif Bio shared in an interview with Contagion®. “The reasons the options are limited in this population and why there are poor outcomes among diabetics are because antibiotics, especially bacteriostatic antibiotics, may not work as well in immunocompromised hosts, when higher blood sugar levels weaken the immune system, micro and macroangiopathies may limit distribution of an antibiotic, especially larger antibiotics, to the site of infection, gastrointestinal and renal impairment may limit antibiotic absorption and excretion to areas of infection or worsen the function of these organs, comorbidities or drug-drug interactions may limit antibiotics to be coadministered with drugs to treat their diabetes and/or cardiovascular disease. Diabetics often have comorbidities which also may be a risk factor for worsened clinical outcomes.”

“Iclaprim could potentially solve these issues,” continued Dr. Huang, “Because it is bactericidal and may work among immunocompromised populations, including patients with diabetes, as well as patients with peripheral vascular disease who have micro- and macroangiopathies because it is a small molecule, activity is not affected among patients with gastrointestinal and renal impairment because it is metabolized by CYP 3A4 and 2D19 liver enzymes, does not cause nephrotoxicity and has limited, to no, clinically significant drug-drug interactions that would require dose adjustment of iclaprim.

Iclaprim is a novel investigational antibiotic that is effective against gram-positive multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus, with activity against some gram-negative bacteria, including Haemophilus influenzae and Moraxella catarrhalis. Its unique mechanism of action, which involves interfering with dihydrofolate reductase has the drug manufacturer, MotifBio, positioning it as a targeted gram-positive antibiotic. (Only 1 other drug, trimethoprim, has the same target.) The results of previous studies, such as REVIVE-1 and REVIVE-2, previously reported on in Contagion®, have shown that iclaprim is noninferior to vancomycin for the treatment of ABSSSIs.

For this post-hoc study, investigators analyzed data from the REVIVE studies to determine the safety of iclaprim versus vancomycin for the treatment of ABSSSI among patients with diabetes. After first identifying those patients in the study with diabetes, the investigators evaluated the patients “for safety on the basis of medical history and physical examinations, routine electrocardiography, laboratory tests, urinalysis and reports of clinical AEs,” according to the study abstract. Investigators were blinded to each treatment assignment; however, they categorized AE severity and relationship to the study drug. Cockcroft-Gault formula was used to determine baseline renal impairment.

The study results revealed that 11% (n = 127) of the patients in the Intention To Treat (ITT) arm of the REVIVE studies had diabetes, and 37.8% had some type of renal impairment. A total of 71 patients were treated with vancomycin, while 56 were treated with iclaprim. Among the patients in the pooled ITT population, renal impairment was common. Twenty-two (39.2%) of the 56 patients with diabetes in the iclaprim group had mild, moderate, or severe renal impairment, while 26 (36.6%) of the 71 patients in the vancomycin group had such impairment.

AEs were found to be “numerically lower in the iclaprim group compared with the vancomycin group,” according to the study abstract. A total of 3 patients in the vancomycin arm developed acute kidney injury and increased creatine levels, while none of the patients in the iclaprim arm developed these renal AEs in the REVIVE studies. Two (3.6%) of the patients in the iclaprim arm discontinued the study due to an AE, versus 7 (10%) patients in the vancomycin arm.

According to the investigators, diabetic patients treated with iclaprim numerically experienced fewer AEs than patients treated with vancomycin (48.2% vs 52.9%). Patients with diabetes and renal impairment may be more vulnerable to vancomycin-related AEs, and therefore, the investigators state that further evaluation is warranted, particularly in light of the frequent occurrence of diabetes among hospitalized ABSSSI patients, and the broad use of vancomycin in hospital settings.

“Motif continues to perform post-hoc analyses from the REVIVE trials that include clinical efficacy and safety among subpopulations, microbiological responses among different pathogens identified in the trials, and pharmacokinetic and pharmacodynamic analyses among various efficacy and safety parameters and different subpopulations,” concluded Dr. Huang. “In addition, iclaprim has been shown to suppress bacterial toxin suppression in in vitro studies, which may impact outcomes especially among patients with necrotizing infections (skin and pneumonia).”

MotifBio submitted, and had accepted, a New Drug Application for iclaprim in August 2018. It was also granted priority review for the treatment of ABSSSIs and the Prescription Drug User Fee Act (PDUFA) is currently slated for February 13, 2019.