What is the recommended treatment and dosage for complicated urinary tract infections (cUTI) using Plazomicin?

Plazomicin for Complicated Urinary Tract Infections

Recommended Dosage Regimen

Plazomicin 15 mg/kg IV every 24 hours for 4-7 days is the FDA-approved dosage for complicated urinary tract infections (cUTI) in adults with normal renal function (creatinine clearance ≥90 mL/min). 1

Standard Dosing by Renal Function

• For patients with CLcr ≥60 to <90 mL/min: Administer 15 mg/kg IV every 24 hours 1
• For patients with CLcr ≥30 to <60 mL/min: Reduce dose to 10 mg/kg IV every 24 hours 1
• For patients with CLcr ≥15 to <30 mL/min: Administer 10 mg/kg IV every 48 hours 1
• For patients with CLcr <15 mL/min or on dialysis: Insufficient data exists to recommend a dosage regimen 1

Treatment Duration

• The maximum duration of plazomicin therapy for cUTI is 7 days 1
• After 4-7 days of IV plazomicin, consider switching to appropriate oral therapy to complete a total treatment duration of 7-10 days (IV plus oral) 1
• For men with cUTI, consider 14 days total duration when prostatitis cannot be excluded 2

Therapeutic Drug Monitoring Requirements

For all cUTI patients with renal impairment (CLcr 15 to <90 mL/min), therapeutic drug monitoring is mandatory to maintain plasma trough concentrations below 3 mcg/mL. 1, 3

TDM Protocol

• Measure plazomicin plasma trough concentration within approximately 30 minutes before administration of the second dose 1
• If trough concentration is ≥3 mcg/mL: Extend the dosing interval by 1.5-fold (from every 24 hours to every 36 hours, or from every 48 hours to every 72 hours) 1, 3
• The 3 mcg/mL threshold reduces nephrotoxicity risk while maintaining efficacy 3

Daily Renal Function Monitoring

• Assess creatinine clearance in all patients prior to initiating therapy 1
• Monitor creatinine clearance daily during plazomicin therapy 1
• Adjust dosing based on changes in renal function 1

Clinical Efficacy Evidence

Noninferiority to Meropenem

• In the phase 3 EPIC trial (n=609), plazomicin demonstrated noninferiority to meropenem for cUTI treatment 4
• Composite cure at test-of-cure visit: plazomicin 81.7% vs. meropenem 70.1% (difference +11.6 percentage points, 95% CI 2.7-20.3) 4
• Plazomicin showed superior microbiologic eradication rates against ESBL-producing Enterobacteriaceae (82.4% vs. 75.0%) 4
• Lower rates of microbiologic recurrence (3.7% vs. 8.1%) and clinical relapse (1.6% vs. 7.1%) compared to meropenem 4

Role in Multidrug-Resistant Infections

Plazomicin is specifically recommended for cUTI caused by carbapenem-resistant Enterobacteriaceae (CRE) at 15 mg/kg IV every 12 hours, though this represents a weak recommendation with very low quality evidence. 5

Activity Against Resistant Organisms

• Plazomicin is stable against aminoglycoside-modifying enzymes that compromise traditional aminoglycosides 5
• Active against KPC and OXA-48 producing CRE, with variable activity against MBL-producing strains 5
• In the CARE trial, plazomicin-based regimens for serious CRE infections resulted in fewer deaths (24% vs. 50%) and lower acute kidney injury (16.7% vs. 50%) compared to colistin-based regimens 5

Position Among First-Line Options for Resistant Organisms

• Guidelines recommend plazomicin (15 mg/kg once daily) as a first-line aminoglycoside option for cUTI, particularly when fluoroquinolone resistance is present 2
• Alternative first-line parenteral options include carbapenems (meropenem-vaborbactam, imipenem-cilastatin-relebactam) and newer β-lactam/β-lactamase inhibitor combinations (ceftazidime-avibactam, ceftolozane-tazobactam) 2

Safety Profile and Nephrotoxicity Risk

Nephrotoxicity Incidence

• Serum creatinine increases ≥0.5 mg/dL above baseline occurred in 7.0% of plazomicin-treated patients vs. 4.0% with meropenem 4
• Most serum creatinine increases were ≤1 mg/dL above baseline and reversible 1
• Adverse reactions associated with renal function occurred in 3.6% of plazomicin patients vs. 1.3% with meropenem 1

Contraindications and Warnings

• Contraindicated in patients with known hypersensitivity to any aminoglycoside 1
• May cause neuromuscular blockade, ototoxicity, and fetal harm in pregnant women 6
• Not recommended for patients with severe renal impairment including those on renal replacement therapy due to insufficient data 6

Administration Details

Preparation and Infusion

• Supplied as 500 mg/10 mL (50 mg/mL) single-dose vials 1
• Dilute appropriate volume in 0.9% Sodium Chloride or Lactated Ringer's to achieve final volume of 50 mL for IV infusion 1
• Do not mix with other drugs or infuse simultaneously through the same IV line 1
• Diluted solution stable for 24 hours at room temperature or 7 days refrigerated (2-8°C) 1

Dosing Weight Calculations

• Calculate dosage using total body weight (TBW) 1
• For patients with TBW >25% above ideal body weight (IBW): Use adjusted body weight = IBW + 0.4 × [TBW – IBW] 1
• For CLcr estimation using Cockcroft-Gault formula: use TBW, or IBW if TBW exceeds IBW by ≥25% 1

Key Clinical Pitfalls to Avoid

• Failure to implement TDM in renally impaired patients increases nephrotoxicity risk without improving efficacy 3
• Using plazomicin beyond 7 days for cUTI exceeds FDA-approved maximum duration 1
• Inadequate daily renal function monitoring may miss opportunities for dose adjustment 1
• Attempting to use plazomicin in patients on dialysis is not supported by available data 1, 6