What is the recommended use of Plazomicin (plazomicin) for treating complicated urinary tract infections (cUTI) and pyelonephritis?

Recommended Use of Plazomicin for Complicated Urinary Tract Infections (cUTI) and Pyelonephritis

Plazomicin is recommended at a dose of 15 mg/kg intravenously once daily for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, but should only be considered in patients with early culture results indicating the presence of multidrug-resistant organisms when other treatment options are limited. 1, 2

Indications and Positioning in Treatment Algorithm

• Plazomicin is FDA-approved for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, in adults with limited or no alternative treatment options 2
• Plazomicin should not be used as first-line empiric therapy for uncomplicated pyelonephritis; it should be reserved for cases where multidrug-resistant organisms are confirmed 1
• For empiric treatment of uncomplicated pyelonephritis requiring hospitalization, fluoroquinolones, aminoglycosides (with or without ampicillin), or extended-spectrum cephalosporins/penicillins are preferred first-line options 1
• Carbapenems and novel broad-spectrum antimicrobial agents like plazomicin should only be considered when culture results indicate multidrug-resistant organisms 1

Dosing Recommendations

• The recommended dose for adults with normal renal function is 15 mg/kg intravenously once daily 1, 2, 3
• Treatment duration is typically 4-7 days for cUTI 2, 3
• Dosage adjustments are required for patients with renal impairment 2, 4:
  • Therapeutic drug monitoring (TDM) should be implemented for patients with renal impairment to reduce nephrotoxicity risk 4
  • A trough concentration threshold of 3 μg/mL is recommended to balance efficacy and safety in patients with renal impairment 4

Efficacy for cUTI and Pyelonephritis

• Plazomicin demonstrated noninferiority to meropenem in the treatment of cUTI and pyelonephritis in the EPIC trial 3, 5
• At the test-of-cure visit, composite cure (clinical cure and microbiological eradication) was observed in 81.7% of plazomicin-treated patients compared to 70.1% in the meropenem group 3
• Plazomicin showed superior microbiological eradication rates against resistant pathogens, including:
  • Enterobacteriaceae not susceptible to aminoglycosides (78.8% vs. 68.6%) 3
  • Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (82.4% vs. 75.0%) 3
• Lower rates of microbiological recurrence (3.7% vs. 8.1%) and clinical relapse (1.6% vs. 7.1%) were observed with plazomicin compared to meropenem at late follow-up 3

Special Considerations for Carbapenem-Resistant Enterobacteriaceae (CRE)

• Plazomicin is specifically recommended for cUTI due to CRE when other options are limited 1
• Plazomicin is stable against aminoglycoside-modifying enzymes that compromise traditional aminoglycosides 1, 6
• It is active against KPC and OXA-48 producing CRE but has variable activity against metallo-β-lactamase (MBL)-producing strains 1, 6
• In the CARE trial, plazomicin-based combination regimens for serious CRE infections resulted in numerically fewer deaths (24% vs. 50%) and lower acute renal injury (16.7% vs. 50%) compared to colistin-based regimens 1, 6

Safety Considerations and Adverse Effects

• Common adverse reactions include decreased renal function, diarrhea, hypertension, headache, nausea, vomiting, and hypotension 5
• Serum creatinine increases of ≥0.5 mg/dL above baseline occurred in 7.0% of plazomicin-treated patients versus 4.0% in meropenem-treated patients 3
• As with other aminoglycosides, plazomicin carries risks of 2, 5:
  • Nephrotoxicity
  • Ototoxicity
  • Neuromuscular blockade
  • Fetal harm in pregnant women
• Plazomicin is not recommended in patients with severe renal impairment, including those on renal replacement therapy 5

Alternative Treatment Options for cUTI/Pyelonephritis

• For uncomplicated pyelonephritis requiring IV therapy, consider these alternatives before plazomicin 1:
  • Fluoroquinolones: Ciprofloxacin 400 mg IV twice daily or levofloxacin 750 mg IV daily
  • Cephalosporins: Ceftriaxone 1-2 g IV daily, cefotaxime 2 g IV three times daily, or cefepime 1-2 g IV twice daily
  • Penicillins: Piperacillin/tazobactam 2.5-4.5 g IV three times daily
  • Other aminoglycosides: Gentamicin 5 mg/kg IV daily or amikacin 15 mg/kg IV daily
• For CRE infections, other options include 1:
  • Ceftazidime-avibactam 2.5 g IV every 8 hours
  • Meropenem-vaborbactam 4 g IV every 8 hours
  • Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours

Key Pitfalls to Avoid

• Do not use plazomicin as empiric therapy for uncomplicated UTIs or pyelonephritis without evidence of multidrug-resistant organisms 1
• Monitor renal function closely during treatment due to potential nephrotoxicity 2, 3
• Implement therapeutic drug monitoring in patients with renal impairment to minimize toxicity 4
• Avoid use in patients with severe renal impairment 5
• Do not use plazomicin in pregnant women due to potential fetal harm 2