Improved Outcomes at Late Follow-up (LFU) with Plazomicin Compared with Meropenem in Patients with Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) in the EPIC Study

Background: The urinary tract is a common source for multidrug-resistant (MDR) gram-negative infections. The recurrent nature of cUTI leads to frequent antibiotic exposure with attendant potential for resistance development. Plazomicin, a next-generation aminoglycoside with in vitro activity against MDR Enterobacteriaceae, demonstrated non-inferior efficacy to meropenem for treatment of cUTI, including AP, and significantly higher microbiological eradication rates at the test-of-cure (TOC) visit in the EPIC study (Cloutier DJ, et al. ASM 2017). Here, we present the impact of these findings on subsequent microbiological and clinical outcomes at the LFU visit.

Methods: In this randomized, double-blind study, hospitalized patients with cUTI or AP were randomized to intravenous (IV) plazomicin (15 mg/kg q24h) or IV meropenem (1 g q8h), with optional oral step down, for a total of 7-10 days of therapy. Composite cure (combined microbiological eradication and clinical cure), microbiological eradication (reduction of baseline pathogen to <10⁴ CFU/mL), and clinical cure rates were assessed in the microbiological modified intent-to-treat (mMITT) population at the TOC (Day 15-19) and LFU (Day 24-32) visits. Microbiological recurrence and clinical relapse were assessed at LFU in patients who achieved microbiological eradication or clinical cure at the TOC visit, respectively.

Results: At TOC, plazomicin demonstrated a significantly higher composite cure rate than meropenem, driven primarily by a higher microbiological eradication rate in the plazomicin group (Table 1). A significant difference in composite cure rates favoring plazomicin was also observed at the LFU visit. This was driven by both a lower microbiological recurrence and clinical relapse rate in the plazomicin group (Table 2). Most clinical relapses occurred in patients with asymptomatic bacteriuria at the prior TOC visit.

Conclusion: These results demonstrate that asymptomatic bacteriuria is associated with subsequent clinical consequences and suggest that the sustained and differentiated microbiological effect seen with plazomicin, compared with meropenem, may confer a long-term clinical benefit for patients with cUTI, including AP. Further studies are warranted.