By Emily Mui, PharmD

Infectious Disease Pharmacist, Antimicrobial Stewardship Program, Stanford University School of Medicine

Dr. Mui reports no financial relationships relevant to this field of study.

Plazomicin is a next-generation aminoglycoside with potent in-vitro activity against Gram-negative aerobic organisms, including extended spectrum beta-lactamase (ESBL) and carbapenemase-producing Enterobacteriaceae and in-vitro activity against some Gram-positive organisms. On June 26, the Food and Drug Administration (FDA) approved plazomicin for treating complicated urinary tract infections, including pyelonephritis. In a Phase III trial, researchers compared plazomicin to meropenem (with the option to switch to oral levofloxacin) for the primary composite cure endpoint of microbiologic eradication and clinical cure at the end of therapy. In the non-inferiority trial, plazomicin achieved higher microbiological eradication at the test-of-cure visit.1,2

In a Phase III, open-label study consisting of a randomized, open-label cohort and a separate single-arm, observational cohort, investigators examined the efficacy and safety of plazomicin plus meropenem or tigecycline compared to colistin plus meropenem or tigecycline in patients who had serious infections caused by carbapenem-resistant Enterobacteriaceae (CREs), the primary endpoint of all-cause mortality and significant disease-related complications favored patients treated with plazomicin compared to colistin (23.5% vs. 50%; -26.5 (-51.2, 0.7). The secondary endpoint of all-cause mortality at day 28 was lower for the plazomicin group compared to colistin (11.8% vs. 40%; -28.2 (-52.5, -0.07).3,4

MICROBIOLOGY

Plazomicin exhibited in vitro activity that was more potent against most Gram-negative and Gram-positive pathogens than amikacin, gentamicin, and tobramycin. The FDA susceptibility breakpoint for plazomicin against Enterobacteriaceae is ≤ 2 mcg/mL, with isolates with an MIC of 4 mcg/mL considered intermediate and 8 mcg/mL considered resistant. Plazomicin’s MIC50 and MIC90 values are comparable or lower than comparator aminoglycosides against Escherichia coli, Klebsiella pneumoniae, Citrobacter spp., Enterobacter spp., and Serratia spp. (MIC90 values in the range of 0.5-2 mcg/mL). Plazomicin is less active against Proteus mirabilis and indole-positive Proteus spp. (MIC90 values of 4-8 mcg/mL).5-14

Plazomicin has less activity against nonfermentative bacteria (MIC90 values of 16-32 mcg/mL for Pseudo-monas aeruginosa and 16 mcg/mL for Acinetobacter spp.) and is inactive against Stenotrophomonas maltophilia with MIC90 values > 64 mcg/mL.

The mechanisms of resistance to aminoglycosides in Gram-negative bacteria include: reduced drug penetration and/or increased efflux; production of aminoglycoside modifying enzymes (AMEs); and alteration of the ribosomal binding site. Resistance to the other aminoglycosides frequently is caused by AME production, and plazomicin resistance is mostly the result of ribosomal modification. As with other aminoglycoside medications, plazomicin is not active against bacterial isolates that produce 16S rRNA ribosomal methyltransferases.

PHARMACOKINETICS/PHARMACODYNAMICS

Oral absorption of plazomicin has not been studied, but is likely to be low since the bioavailability of aminoglycosides is low. In healthy adults, the mean volume of distribution of plazomicin is 17.9 (±4.8), and approximately 20% is bound to plasma protein. The Cmax and Cmin is approximately 73.7 (±19.7) mcg/mL and 0.3 (±0.2) mcg/mL, respectively. Plazomicin is not metabolized by the liver and is cleared by the kidneys primarily as unchanged drug in the urine. The average half-life of plazomicin is 3.5 hours in healthy adults with normal renal function (n = 54). The pharmacokinetic/pharmacodynamic parameter that best correlates with efficacy against Enterobacteriaceae is area under the plasma concentration-time curve to the minimum inhibitory concentration (AUC:MIC).1

ADVERSE EFFECTS/WARNINGS

For patients with known hypersensitivity to any aminoglycoside medication, plazomicin is contraindicated.1

Nephrotoxicity has been reported with plazomicin use. In trial 1 of the complicated UTI clinical trials, the incidence of renal function-associated adverse reactions was 3.6% in patients treated with plazomicin compared to 1.3% for patients treated with meropenem. Most increases in serum creatinine were 1 mg/dL above baseline and were reversible on discontinuation of the drug. In trial 1 and trial 2, the nephrotoxicity incidence was higher for patients with trough levels 3 mcg/mL (36%, 10/28) than for patients with plazomicin Cmin < 3 mcg/mL (5%, 11/215). Trough levels of 3 mcg/mL were associated with an increase in SCr of 0.5 mg/dL or more above baseline and occurred in 7% of patients treated with plazomicin compared to 4% in those treated with meropenem.1

Ototoxicity, including hearing loss, tinnitus, and vertigo, has been reported with plazomicin. The ototoxicity associated with aminoglycosides may not be reversible and may not be evident until after therapy is finished. In clinical trials, there was one case of reversible hearing impairment, one case of irreversible tinnitus, and one case of reversible vertigo. (Of note, one case of tinnitus occurred in the meropenem arm and one case of an abnormal audiogram occurred in a patient treated with levofloxacin).1

PREGNANCY AND LACTATION

Aminoglycoside antibiotics can cause harm to the fetus when administered to pregnant women. Reports of irreversible congenital deafness have been reported with streptomycin. Data are lacking regarding plazomicin in human milk, the effects on breastfed infants, or the effect of the drug on milk production. Approximately 2-4% of maternal plasma concentrations is detected in rat milk.1

CONCLUSION

Plazomicin is a new drug in the aminoglycoside class that is indicated for treatment of complicated UTIs, including pyelonephritis. Unlike other aminoglycosides, plazomicin is resistant to the effect of enzymatic inactivation by common AMEs and has potent activity against ESBL and CREs. Plazomicin also may have an adjunctive role in salvage therapy in serious CRE infections.

REFERENCES

  1. Zemdri® [package insert]. South San Francisco, CA: Achaogen, Inc.; 2018.
  2. Cloutier DJ, Miller LG, Komarenko 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). American Society for Microbiology Microbe; June 1-5, 2017. New Orleans, LA.
  3. Connolly LE, Jubb A, O’Keefe B, et al. Plazomicin (PLZ) associated with improved survival and safety compared to colistin (CST) in serious carbapenem-resistant Enterobacteriaceae (CRE) infections: Results of the CARE study. American Society for Microbiology Microbe; June 1-5, 2017; New Orleans, LA. Abstract 5831.
  4. McKinnell JA, Connolly LE, Pushkin R, et al. Improved outcomes with plazomicin compared with colistin in patients with bloodstream infections caused by carbapenem-resistant Enterobacteriaceae (CRE): Results from the CARE study. IDWeek; October 4-8, 2017; San Diego, CA. Poster 1853.
  5. Aggen JB, Armstrong ES, Goldblum AA, et al. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob Agents Chemother 2010;54:4636.
  6. Almaghrabi R, Clancy CJ, Doi Y, et al. Carbapenem-resistant Klebsiella pneumoniae strains exhibit diversity in aminoglycoside-modifying enzymes, which exert differing effects on plazomicin and other agents. Antimicrob Agents Chemother 2014;58:4443.
  7. Endimiani A, Hujer KM, Hujer AM, et al. ACHN-490, a neoglycoside with potent in vitro activity against multidrug-resistant Klebsiella pneumoniae isolates. Antimicrob Agents Chemother 2009;53:4504.
  8. Galani I, Souli M, Daikos GL, et al. Activity of plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece. J Chemother 2012;24:191.
  9. Landman D, Babu E, Shah N, et al. Activity of a novel aminoglycoside, ACHN-490, against clinical isolates of Escherichia coli and Klebsiella pneumoniae from New York City. J Antimicrob Chemother 2010;65:2123.
  10. Landman D, Kelly P, Backer M, et al. Antimicrobial activity of a novel aminoglycoside, ACHN-490, against Acinetobacter baumannii and Pseudomonas aeruginosa from New York City. J Antimicrob Chemother 2011;66:332.
  11. Livermore DM, Mushtaq S, Warner M, et al. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J Antimicrob Chemother 2011;66:48.
  12. Rodriguez-Avial I, Pena I, Picazo JJ, et al. In vitro activity of the next-generation aminoglycoside plazomicin alone and in combination with colistin, meropenem, fosfomycin or tigecycline against carbapenemase-producing Enterobacteriaceae strains. Int J Antimicrob Agents 2015;46:616.
  13. Walkty A, Adam H, Baxter M, et al. In vitro activity of plazomicin against 5,015 gram-negative and gram-positive clinical isolates obtained from patients in Canadian hospitals as part of the CANWARD study, 2011-2012. Antimicrob Agents Chemother 2014;58:2554.

Table: Dosing1

Estimated CrCL (mL/min)

Dosage

CrCL ≥ 90 mL/min

15 mg/kg IV Q24H

60-90 mL/min

15 mg/kg IV Q24H

30-60 mL/min

10 mg/kg Q24H

15-30 mL/min

10 mg/kg Q48H

Therapeutic drug monitoring is recommended in patients who have creatinine clearance between 15-90 mL/min. The goal plazomicin trough < 3 mcg/mL.