From Pages to Practice
Published April 3, 2019
In 1944, the first aminoglycoside — streptomycin — was isolated from a strain of Streptomyces griseus in farm soil at Rutgers University. Since then, this class of broad-spectrum antibiotics, which inhibit protein synthesis, has expanded considerably. However, beginning in the 1980s, reports of adverse effects, including neurotoxicity and ototoxicity, resulted in a shift away from systemic use of aminoglycosides to other antibiotics.
Now, our options for treating infections are shrinking due to increasing multidrug resistance in bacteria. A renewed interest has emerged in the development of agents active against antibiotic resistant bacteria. Complicated urinary tract infections (UTIs) are often caused by gram-negative bacteria, providing a potential clinical circumstance to demonstrate activity of a new antibacterial agent. Complicated UTIs are associated with additional risk factors including indwelling catheter, recent antibiotic use, and anatomical abnormalities. But many bacterial strains now produce aminoglycoside-modifying enzymes, which result in resistance. Plazomicin is an engineered aminoglycoside that is not affected by aminoglycoside-modifying enzymes. It was approved by the FDA in June 2018 for treatment of complicated UTI.
The recently published multicenter, randomized, double-blind Evaluating Plazomicin in Complicated UTI (EPIC) trial demonstrated that plazomicin was noninferior to meropenem for the treatment of complicated UTI.
The following NEJM Journal Watch summary further explains the study and its findings.
A noninferiority trial supported the drug's approval for this use.
To test noninferiority of the novel aminoglycoside antibiotic plazomicin to meropenem in treating complicated urinary tract infection (UTI), researchers conducted a manufacturer-sponsored study. They blindly randomized 601 patients to receive plazomicin (15 mg/Kg intravenously once daily) or meropenem (1g IV every 8 hours) for a total of 10 days, including an option to step down to oral antibiotic after at least 4 days of study drug. The primary study endpoints were composite cure (clinical cure and microbiologic eradication) at day 5 and at test of cure (TOC; 15–19 days after start of treatment) among patients who were randomized, received at least one dose of study drug, and had a cultured pathogen susceptible to meropenem and plazomicin.
Day-5 composite cure occurred in 88% (168/191) with plazomicin and 91% (180/197) with meropenem, a nonsignificant difference. At TOC, composite cure was observed in 82% of plazomicin recipients and 70% meropenem recipients (a significant difference of 11.6%). This difference rested on microbiologic eradication; clinical cure rates were not significantly different. At TOC, differences remained statistically significantly better for plazomicin therapy for patients <65 years old, baseline creatinine clearance of >60 mL/min, no urinary catheter, and female patients. Fewer plazomicin recipients had microbiologic recurrence (3.7 vs. 8.1%) and clinical relapse (1.6 vs. 7.1%) at 4-week follow-up. Both treatments were well-tolerated; serum creatinine elevations ≥0.5 mg/dL above baseline occurred in 4% and 7% of meropenem and plazomicin treatments, respectively.
Comment: These data led to plazomicin's approval for treating complicated UTI (NEJM JW Infect Dis Sep 2018). In addition, this study offers some clinical reminders. Short-course aminoglycoside therapy (mean intravenous therapy duration in this study, 5.5 days) is safe, particularly in patients without underlying kidney disease. Asymptomatic bacteriuria that remains after completion of therapy is largely yet not completely benign, offering fodder for relapsing infection that might be minimized with an aminoglycoside instead of a β-lactam. Unfortunately, this product's future remains uncertain as the manufacturer's finances are in dire straits (https://seekingalpha.com/article/4241037-cash-running-short-time-running-achaogen).