By Marie Rosenthal

The FDA approved plazomicin (Zemdri, Achaogen) for the treatment of adults with complicated urinary tract infections (cUTIs), including pyelonephritis, but rejected a request for a bloodstream infection (BSI) indication.

The aminoglycoside will be given as a once-daily IV infusion. Plazomicin will be indicated for cUTIs, including pyelonephritis, caused by certain Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum beta-lactamases (ESBL), in patients with limited or no alternative treatment options. It is indicated for the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Enterobacter cloacae.

“Bacteria continue to circumvent existing antibiotics, making certain infections notoriously hard to treat and putting some patients at high risk for mortality,” said James A. McKinnell, MD, an assistant professor of medicine at the David Geffen School of Medicine at UCLA and LA BioMed at Harbor-UCLA Medical Center, in Los Angeles. “Aminoglycosides are a familiar and very effective class of antibiotics.”

Plazomicin was engineered to overcome aminoglycoside-modifying enzymes, the most common aminoglycoside resistance mechanism in Enterobacteriaceae, and has in vitro activity against ESBL-producing, aminoglycoside- resistant and CRE isolates. 

The approval of plazomicin is supported partly by data from the EPIC (Evaluating Plazomicin In cUTI) clinical trial, which was a randomized, controlled study of once-daily aminoglycoside therapy for the treatment of cUTIs, including pyelonephritis.

In the phase 3 EPIC cUTI trial, plazomicin was noninferior to meropenem for the coprimary efficacy end points of composite cure (clinical cure and microbiological eradication) in the microbiological modified intent-to-treat (n=388) population at day 5 and test-of-cure (TOC) visit (day 15-19). 

Composite cure rates at day 5 were 88.0% (168/191) for plazomicin versus 91.4% (180/197) for meropenem (difference, –3.4%; 95% CI, –10.0 to 3.1). Composite cure rates at TOC visit were 81.7% (156/191) for plazomicin versus 70.1% (138/197) for meropenem (difference, 11.6%; 95% CI, 2.7-20.3). Composite cure at the TOC visit in patients with concomitant bacteremia at baseline was achieved in 72.0% (18/25) of patients in the plazomicin group and 56.5% (13/23) in the meropenem group. 

Each year, an estimated 3 million cUTIs, defined as a UTI occurring in a patient with an underlying complicating factor of the genitourinary tract, such as a structural or functional abnormality, are treated in a U.S. hospital setting.

In approving plazomicin for cUTIs and not for BSI, the FDA followed the recommendations of the FDA Antimicrobial Drugs Advisory Committee, which found that the BSI study, CARE (Combating Antibiotic Resistant Enterobacteriaceae), did not provide substantial efficacy data to support the approval of plazomicin for the treatment of BSIs. Achaogen said it would meet with the FDA to see whether there is something it can do to get this BSI indication.

Plazomicin should be limited for use in cUTI patients who have limited or no alternative treatment options.

Plazomicin will carry a boxed warning against nephrotoxicity, ototoxicity, neuromuscular blockade and fetal harm:

• The risk for nephrotoxicity is greater in patients with impaired renal function, in the elderly and in those receiving concomitant nephrotoxic medications. Assess creatinine clearance in all patients before initiating therapy and daily during therapy. Therapeutic drug monitoring is recommended for cUTI patients with a creatinine clearance less than 90 mL per minute to avoid potentially toxic levels.
• Ototoxicity manifested as hearing loss, tinnitus and/or vertigo. Symptoms of aminoglycoside-associated ototoxicity may be irreversible and may not become evident until after completion of therapy. Aminoglycoside-associated ototoxicity has been observed primarily in patients with a family history of hearing loss, patients with renal impairment, and in patients receiving higher doses and/or longer durations of therapy than recommended.
• During therapy with plazomicin, monitor for adverse reactions associated with neuromuscular blockade, particularly in high-risk patients, such as those with underlying neuromuscular disorders (e.g., myasthenia gravis) or in patients concomitantly receiving neuromuscular blocking agents.
• Aminoglycosides, including plazomicin, can cause fetal harm when given to a pregnant woman.

For the full prescribing information, click here.