By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a new semi-synthetic aminoglycoside for the treatment of complicated urinary tract infections (cUTI). Plazomicin received priority review and orphan status designation. It is marketed as Zemdri.
Plazomicin is indicated for the treatment of adults ≥ 18 years of age with cUTI, including pyelonephritis caused by susceptible microorganism(s) Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae.1
The recommended dose is 15 mg/kg every 24 hours, administered intravenously over 30 minutes for four to seven days in patients with creatinine clearance ≥ 60 mL/min.1 For patients with creatinine clearance > 30 mL/min (but < 60 mL/min), the dose is 10 mg/kg every 24 hours. For those with creatinine clearance < 30 mL/min, the dose is 10 mg/kg every 48 hours. Therapeutic drug monitoring is recommended in patients with renal impairment to ensure that the plasma trough level is below 3 mcg/mL. Plazomicin is available as 500 mg single-dose vials.
Plazomicin has shown in vitro bactericidal activity against aminoglycoside and beta-lactam-resistant, multidrug-resistant Enterobacteriaceae isolates.2,3 It retains activity against many strains that produce aminoglycoside-modifying enzymes, making it more active compared to traditional aminoglycosides.4
Plazomicin shares the same basic boxed warnings as other aminoglycosides, namely nephrotoxicity, ototoxicity, neuromuscular blockade, and fetal toxicity.1 Microorganisms that produce metallo-beta-lactamases may be resistant to plazomicin.1 The manufacturer hoped to receive FDA approval for blood stream infections; however, the agency declined approval, citing inadequate evidence of efficacy.5
The approval of plazomicin was based mainly on a randomized, double-blind, noninferiority, active-controlled trial in subjects with cUTI (including 42% with pyelonephritis).1,7 Subjects were randomized to plazomicin (15 mg/kg once daily) or meropenem (1 g intravenously every eight hours). Switching to an oral antibacterial was allowed after a minimum of four days or a maximum of seven days of intravenous therapy. The total duration of treatment was seven to 10 days. Efficacy was assessed based on a microbiological-modified intent-to-treat (mMITT) analysis that included subjects who received the study medication and exhibited at least one baseline uropathogen. Those with organisms resistant to study drugs were excluded. The mMITT population included 191 subjects in the plazomicin group and 197 subjects in the meropenem group. Efficacy endpoints were composite cure at day 5 and composite cure at the test-of-cure (TOC) visit at day 17 (± 2). Composite cure was defined as resolution or improvement of clinical cUTI symptoms and microbiological eradication (uropathogens reduced to < 104 colony-forming units). Cure rates were 88% for plazomicin compared to 91.4% for meropenem on day 5, and 81.7% vs. 70.1% for day 17. Both met the criteria for noninferiority, with a significantly higher cure rate at TOC. Microbiological eradication also favored plazomicin at TOC (89.5% vs. 74.6%).
According to the CDC, untreatable and hard-to-treat infections from multiple drug-resistant, carbapenem-resistant Enterobacteriaceae (CRE) bacteria are on the rise among patients in medical facilities.6 The mortality rate is nearly 50% for hospital patients who contract bloodstream infections from CRE bacteria.6 Plazomicin joins the new beta-lactamase inhibitor combinations (meropenem-vaborbactam and ceftazidime-avibactam) against CREs for cUTIs. Plazomicin provides another option. Its use should be determined by patients’ clinical features and bacteria susceptibility.8 The FDA informed the manufacturer that there was insufficient evidence to approve the drug for the treatment of bloodstream infection, which may limit its utility.9
- Zemdri Prescribing Information, Achaogen, Inc., June 2018. Available at: . Accessed July 24, 2018.
- Thwaites M, Hall D, Shinabarger D, et al. Evaluation of the bactericidal activity of plazomicin and comparators against multidrug-resistant Enterobacteriaceae. Antimicrob Agents Chemother 2018 Jun 4. pii: AAC.00236-18. doi: 10.1128/AAC.00236-18. [Epub ahead of print].
- Castanheira M1, Davis AP2, Mendes RE et al. In vitro activity of plazomicin against gram-negative and gram-positive isolates collected from United States hospitals and comparative activity of aminoglycosides against carbapenem-resistant Enterobacteriaceae and isolates carrying carbapenemase genes. Antimicrob Agents Chemother 2018 Jun 4. pii: AAC.00313-18. doi: 10.1128/AAC.00313-18. [Epub ahead of print].
- Cox G, Ejim L, Stogios PJ, et al. Plazomicin retains antibiotic activity against most aminoglycoside modifying enzymes. ACS Infect Dis 2018;4:980-987.
- Sagonowsky E. It’s a good news, bad news FDA approval for Achaogen’s powerful antibiotic Zemdri. FiercePharma, June 26, 2018. Available at: . Accessed July 24, 2018.
- Centers for Disease Control and Prevention. Antibiotics/Antimicrobial Resistance: Biggest Threats. Available at: . Accessed July 24, 2018.
- Cloutier DJ, Miller LG, Komirenko AS, et al. Evaluating once-daily plazomicin versus meropenem for the treatment of complicated urinary tract infection and acute pyelonephritis: Results from a phase 3 study (EPIC). Presented at the American Society of Microbiology Microbe, June 1-5, 2017, New Orleans. Available at: . Accessed July 24, 2018.
- Rodríguez-Baño J, Gutiérrez-Gutiérrez B, Machuca I, Pascual A. Treatment of infections caused by extended-spectrum-beta-lactamase-, AmpC-, and carbapenemase-producing Enterobacteriaceae. Clin Microbiol Rev 2018 Feb 14;31(2). pii: e00079-17. doi: 10.1128/CMR.00079-17. [Print 2018 Apr].
- Drugs.com. Achaogen announces FDA advisory committee voted unanimously in favor of plazomicin for treatment of adults with complicated urinary tract infections, May 2, 2018. Available at: . Accessed July 24, 2018.