Plazomicin: A Novel Aminoglycoside

Aminoglycosides date back to the 1940s, with the intro­duction of streptomycin. Streptomycin was the first antibiotic available for the effective treatment of tuber­culosis, netting its discoverer, Selman Waksman, a Nobel Prize. During the golden age of antibiotic development in the 1940s through 1960s, aminoglycosides continued to advance, along with many novel classes of antibiotics. Because of their potent activity against gram-negative organisms, aminoglycosides became mainstays of infectious diseases pharmaco-therapy, before eventually being displaced by broad-spectrum β-lactams, which became widely available in the 1980s and 1990s.

Inevitably, organisms developed resistance mechanisms to aminoglycosides. In Enterobacteriaceae, resistance is commonly due to plasmid-encoded aminoglycoside-modifying enzymes (AMEs). These enzymes cause a change in the chemical structure of the aminoglycoside compound, resulting in lower binding affinity for the bacterial ribosome and high-level resistance to the class. Plazomicin, which was approved by the US Food and Drug Administration (FDA) on June 25, 2018, for the treatment of complicated urinary tract infections (cUTIs), was developed with structural modifications to protect it from AMEs.¹ On August 3, 2018, the Centers for Medicare & Medicaid Services granted plazomicin a new technology add-on payment for inpatient use.

Plazomicin is active against all aminoglycoside-modifying enzymes that confer resistance to older aminoglycosides, except N-acetyltransferase exhibited in Providencia species.² Compared with older aminoglycosides, it has more potent activity against extended-spectrum β-lactamase—producing and carbapenem-resistant Enterobacteriaceae (CRE).^3-5 In an in-vitro comparison with CRE, plazomicin had a minimum inhibitory concentration for 90% of the isolates (MIC90) of 2 mg/mL compared with gentamicin (MIC90 64 mg/mL), tobramycin (MIC90 32 mg/mL), and amikacin (MIC90 32 mg/mL).³ The approved breakpoint for plazomicin is 2 mg/mL.

To date, plazomicin has been studied in 2 significant phase 3 clinical trials. The EPIC trial compared plazomicin with meropenem for the treatment of cUTIs, including acute pyelonephritis (AP), in 388 adults. Plazomicin demonstrated noninferiority in composite cure, defined as achieving micro­biologic eradication and clinical cure, at the test-of-cure visit with a success rate of 81.7% compared with 70.1% with meropenem, a difference of 11.6% (95% CI, 2.7 to 20.3).

Interestingly, patients in the plazomicin arm also experienced a significantly lower rate of clinical relapse at late follow-up compared with those in the meropenem arm (1.8% vs 7.9%).⁵ The FDA granted plazomicin approval for the treatment of cUTI including AP in adults 18 years and older with limited or no available treatment options. The indicated dose is 15 mg/kg intravenously every 24 hours.⁶

Plazomicin was also studied in the CARE trial, a prospec­tive, randomized study of patients with CRE infections. Investigators compared plazomicin with colistin in 37 adult patients with bloodstream infections (BSIs), hospital-acquired pneumonia, and ventilator-associated pneumonia caused by CRE. Patients in the plazomicin arm had a 26.5% lower all-cause mortality or disease-related complication rate compared with those in the colistin arm (23.5% vs 50.0%; 95% CI, —0.7 to 51.2). Patients treated with plazomicin for a BSI demonstrated a survival benefit with a hazard ratio for death of 0.37 (90% CI, 0.15 to 0.91).⁷ In addition, patients with a BSI had a microbiologic response rate of 92.9% when treated with plazomicin compared with 53.3% for those treated with colistin.⁷

Following a single 15-mg/kg intravenous (IV) dose, plazo­micin achieved a maximum concentration of 73.7 mg/mL, a minimum concentration of 0.3 mg/mL, and an area under the curve of 257 mg/mL. The mean volume of distribution is 17.9 L, and protein binding is estimated to be 20%. Plazomicin has a half-life of 3.5 hours in patients with normal renal function and is primarily excreted renally unchanged. Therapeutic drug monitoring can be performed, with a goal trough level of less than 3 mg/mL prior to the second dose to minimize toxicity.⁶ Plazomicin lung penetration was measured at 13% after a single dose in healthy volunteers.⁸

Warnings and precautions associated with plazomicin use are consistent with those reported for older aminoglycosides. Black box warnings include nephrotoxicity, ototoxicity, neuro­muscular blockade, and teratogenicity. Adverse events most commonly observed in clinical studies include acute kidney injury, diarrhea, headache, nausea, vomiting, and hypertension or hypotension.⁶ In the EPIC trial, 3.7% of patients treated with plazomicin had a serum creatinine level increase of ≥0.5 mg/dL while on IV therapy compared with 3.0% of patients treated with meropenem.⁵ In the CARE trial, 11.1% of patients who received plazomicin had serum creatinine level increases compared with 38.1% of those who received colistin.⁷

With its activity against multidrug-resistant Enterobacteriaceae, plazomicin offers an alternative for patients at high risk for, or with a history of, infection caused by organisms such as CRE. Although plazomicin is indicated by the FDA to treat cUTI, there are limited prospective data supporting its use as a treatment for other infections caused by CRE, particularly BSIs. As such, plazomicin may be particularly useful in urosepsis, though its use should be reserved for instances including carbapenem resistance or elevated MICs to older aminoglycosides.

Dr. Heaney is a PGY2 resident in infectious diseases pharmacy at Temple University School of Pharmacy in Philadelphia, Pennsylvania. She completed her PharmD at the University of the Sciences Philadelphia College of Pharmacy and a PGY1 residency at Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania.

Dr. Gallagher is a clinical professor at Temple University School of Pharmacy and clinical pharmacy specialist in infectious diseases at Temple University Hospital, both in Philadelphia, Pennsylvania. He also is the director of the PGY2 Residency in Infectious Diseases Pharmacy at Temple.

References:

1. Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM. Aminoglycosides: activity and resistance. Antimicrob Agents Chemother. 1999;43(4):727-737.
2. Zhanel GG, Lawson CD, Zelenitsky S, et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev Anti Infect Ther. 2012;10(4):459-473.
3. Denervaud-Tendon V, Poirel L, Connolly LE, Krause KM, Nordmann P. Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. J Antimicrob Chemother. 2017;72(10):2787-2791.
4. Haidar G, Alkroud A, Cheng S, et al. Association between the presence of aminoglycoside-modifying enzymes and in vitro activity of gentamicin, tobramycin, amikacin, and plazomicin against Klebsiella pneumoniae carbapenemase- and extended-spectrum-β-lactamase-producing Enterobacter species. Antimicrob Agents Chemother. 2016;60(9):5208-5214.
5. Cloutier D, Miller L, Komirenko A, et al. Evaluating once-daily plazomicin versus meropenem for the treatment of complicated urinary tract infection (cUTI) and acute pyelonephritis (AP): Results from a phase 3 study (EPIC). Presented at: ASM Microbe 2017; June 4, 2017; New Orleans, LA.
6. Plazomicin [package insert]. San Francisco, CA: Achaogen, Inc.; 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303Orig1s000lbl.pdf. Accessed 18 July 2018.
7. Daikos G, Connolly L, Jubb A, et al. Plazomicin (PLZ) associated with improved survival and safety compared to colistin in serious carbapenem-resistant Enterobacteriaceae (CRE) infections: Results of the CARE study. Presented at: ASM Microbe 2017; June 5, 2017; New Orleans, LA.
8. Cass R, Kostrub CF, Gotfried M, Rodvold K, Tack KJ, Bruss J. A double-blind, randomized, placebo-controlled study to assess the safety, tolerability, plasma pharmacokinetics and lung penetration of intravenous plazomicin in healthy subjects. Poster presented at: 23^rd European Congress of Clinical Microbiology and Infectious Diseases; May 1, 2013; Berlin, Germany.