What about using plazomicin for multi-drug resistant Klebsiella infections?

Plazomicin for Multi-Drug Resistant Klebsiella Infections

Plazomicin is recommended primarily for complicated urinary tract infections (cUTI) caused by carbapenem-resistant Klebsiella at 15 mg/kg IV every 12 hours, but should be reserved as an alternative option when newer β-lactam/β-lactamase inhibitor combinations are unavailable or inactive. 1, 2, 3

Primary Role: Complicated Urinary Tract Infections

• Plazomicin is FDA-approved specifically for cUTI caused by carbapenem-resistant Enterobacterales (CRE), including Klebsiella pneumoniae, at a dose of 15 mg/kg IV every 12 hours for 5-7 days. 1, 2, 3

• In the phase III trial, plazomicin demonstrated noninferiority to meropenem with composite cure rates of 81.7% versus 70.1% at test-of-cure visit for cUTI. 3, 4

• For simple cystitis due to CRE, single-dose aminoglycosides (including plazomicin) may be considered as an alternative regimen. 1

Positioning in Treatment Algorithm

For KPC-producing Klebsiella infections, newer β-lactam agents (ceftazidime/avibactam, meropenem/vaborbactam) should be first-line, with plazomicin reserved as an alternative. 1

• The 2022 Italian guidelines provide strong recommendations (moderate certainty) for ceftazidime/avibactam and meropenem/vaborbactam as first-line agents for KPC-producing CRE infections, demonstrating 28-day mortality of 18.3% versus 40.8% for alternative therapies. 1

• Plazomicin is listed alongside other alternatives (imipenem/relebactam, eravacycline) for which insufficient comparative evidence exists. 1

Antimicrobial Activity Profile

Plazomicin demonstrates excellent activity against KPC and OXA-48 producing Klebsiella but has variable activity against metallo-β-lactamase (MBL) producers. 2, 3

• The drug is stable against most aminoglycoside-modifying enzymes (AMEs) that compromise traditional aminoglycosides like gentamicin and amikacin. 3, 4

• Critical limitation: Plazomicin is inactive against bacteria producing 16S rRNA methyltransferases, which often co-exist with MBL-producing strains. 3

• In vitro studies show MIC ranges of 0.12-8 μg/mL against Klebsiella species, with the highest activity demonstrated in recent Greek hospital data (MIC50/MIC90: 0.5/1.5 μg/mL). 5, 6

Use in Bloodstream Infections

For Klebsiella bacteremia, plazomicin-based combination therapy may be considered when first-line agents are unavailable, though evidence is limited. 2, 7

• In the CARE trial, plazomicin-based combinations showed numerically lower mortality compared to colistin-based regimens (24% versus 50%), though this was a small study. 2

• A case report documented successful treatment of multidrug-resistant Klebsiella bacteremia using plazomicin combined with meropenem/vaborbactam in a patient with renal failure. 7

• Important caveat: The ESCMID guidelines note insufficient evidence comparing plazomicin monotherapy versus combination therapy for serious CRE infections. 1, 2

Combination Therapy Considerations

Plazomicin demonstrates synergy with β-lactams (piperacillin/tazobactam, ceftazidime, meropenem) against MDR Klebsiella without antagonism. 3, 5

• Checkerboard and time-kill assays confirm synergistic activity when combined with β-lactams against aminoglycoside-resistant and carbapenemase-producing strains. 5

• No antagonism was observed when combined with colistin, tigecycline, fosfomycin, or other agents. 3

Safety Profile and Monitoring

Plazomicin carries the aminoglycoside class Black Box Warning for nephrotoxicity, ototoxicity, and neuromuscular blockade, but demonstrated favorable safety in clinical trials. 3, 4, 8

• Most common adverse effects include decreased renal function (3.7%), diarrhea (2.3%), hypertension (2.3%), and headache (1.3%). 4, 8

• Critical monitoring requirement: Therapeutic drug monitoring is essential in patients with renal dysfunction, as drug levels can remain persistently elevated. 7

• Dosage reductions are required for moderate-to-severe renal impairment, and the drug is not recommended in patients requiring renal replacement therapy per FDA labeling. 3, 4

• However, successful use with therapeutic drug monitoring has been documented in a patient requiring hemodialysis, suggesting careful monitoring may allow use in this population. 7

Clinical Decision Algorithm

1. Identify carbapenemase type through rapid molecular testing (KPC, OXA-48, MBL). 1

2. For KPC or OXA-48 producers:

   • First-line: Ceftazidime/avibactam or meropenem/vaborbactam 1
   • Alternative for cUTI: Plazomicin 15 mg/kg IV q12h 1, 2

3. For MBL producers:

   • Avoid plazomicin if 16S rRNA methyltransferase co-exists 3
   • Consider ceftazidime/avibactam plus aztreonam combination instead 1

4. For serious infections (bacteremia, pneumonia):

   • Prioritize newer β-lactam combinations over plazomicin 1
   • Consider plazomicin-based combination therapy only when alternatives unavailable 2, 7

Key Pitfalls to Avoid

• Do not use plazomicin for pneumonia: Insufficient evidence exists for this indication, and newer β-lactams have superior data. 1

• Do not assume activity against all CRE: Test for 16S rRNA methyltransferases and MBL production, which confer resistance. 3

• Do not use standard dosing in renal impairment without adjustment and monitoring: Persistently elevated levels increase toxicity risk. 3, 7, 4

• Do not use as monotherapy for serious infections when combination therapy is feasible: Limited evidence supports monotherapy outside of cUTI. 1, 2