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Sulbactam-durlobactam (Xacduro)

Sulbactam-durlobactam photo, courtesy of Dr. Justo

KEY POINTS

  • Sulbactam-durlobactam (Xacduro, SUL-DUR, ETX2514SUL) is the combination of two beta-lactamase inhibitors, it is owned by Entasis Therapeutics and distributed by La Jolla Pharmaceutical Company
    • Although a beta-lacatamase inhibitor, sulbactam is also considered a beta-lactam and has direct activity against Acinetobacter-baumannii-calcoaceticus complex (commonly referred to as Acinetobacter baumannii)
      • Sulbactam is recommended by IDSA guidelines for treatment of Acinetobacter, it can bind to PBP1 and PBP3 on this bacteria, inhibiting bacterial cell wall synthesis
      • Sulbactam has been commercially available in the United States for decades, in combination with ampicillin as ampicillin-sulbactam (Unasyn)
      • Sulbactam can inhibit Ambler Class A enzymes
    • Durlobactam serves to protect sulbactam (and other beta-lactams) by neutralizing beta-lactamases which may otherwise hydrolyze them
      • Durlobactam can inhibit class A, C, and D beta-lactamases. This includes CTX-M, KPC, SHV, TEM, ADC-type, and OXA-type enzymes.
        • You can find a listing of Ambler Class enzymes here
        • Class B enzymes durlobactam does not cover includes IMP, NDM, and VIM which are metallo-beta-lactamases
  • FDA approved 23 May 2023  for patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), cause by susceptible isolates of Acinetobacter-baumannii-calcoaceticus complex
    • Not indicated per FDA approval for any other pathogen
    • In the trial that got it approved by the FDA, sulbactam-durlobactam was given in combination with imipenem-cilastatin (Primaxin)
    • It was compared to colistin (also given with IMI-CIL). It had lower all cause mortality at day 28 at 19% versus 32.3%
      • The number of patients in the m-MITT population was quite small at 63 patients in the sulbactam-durlobactam arm and 62 patients in the colistin arm
        • By nature, this is an incredibly difficult area of study with a great deal of inter patient variability, so low numbers of patients is expected
    • The role of sulbactam-durlobactam in clinical practice will be for carbapenem-resistant Acinetobacter HABP/VABP or clinical cases of Acinetobacter HABP/VABP where alternative drugs are not options (e.g., due to drug allergies or drug-drug interactions)
  • Usual dosing is 1 gram sulbactam plus 1 gram of durlobactam given every 6 hours IV over a 3 hour infusion for 7 to 14 days
    • The pharmacokinetic-pharmacodynamic paramater for sulbactam is time above MIC and for durlobactam is 24-hour unbound AUC
      • Major route of elimination is renal
      • T 1/2 his about 2 hours for both
    • Renal dosing:
      • All doses are given over 3 hours
      • Adjust dose for CrCl of 130 mL/min or more to every 4 hours
        • Note may be encountered in seriously ill patients receiving intravenous fluid resuscitation
      • Adjust dose for CrCl of 30 to 44 mL/min to every 8 hours
      • Adjust dose for CrCl of 15 to 29 mL/min to every 12 hours
      • Adjust dose for CrCl below 15 mL/min to every 12 hours for the first 3 hours, then every 24 hours. If a patient is on therapy and their renal function falls below 15 on therapy, the patient can be changed to every 24 hour dosing (prescribing description advised on case-by-case basis)
      • If given to patients on intermittent hemodialysis, dose should be given immediately following dialysis
  • Has warnings for hypersensitivity reaction and Clostridioides difficile-associated diarrhea
  • Most common adverse reaction was liver test abnormalities, diarrhea, anemia, and hypokalemia
  • Can have drug-drug interactions as with OAT1 inhibitors, concomitant administration not recommended as per package insert
    • OAT1 inhibitors may increase sulbactam concentrations
  • Provided in a co-packaged kit of one sulbactam 1 gram vial plus two durlobactam 0.5 gram amber vials
    • Uncreconstituted vials should be stored under refrigeration and not frozen
    • Both sulbactam and durlobactam vials must be diluted within 1 hour of reconstitution
    • Reconstituted solution from each of the 3 vials is added to one 100 mL normal saline bag for administration (5 mL sulbactam plus 2.5 mL durlobactam from each vial)
    • Only compatible with normal saline
    • Storage is under refrigeration (36F to 46F) once prepared, must be given within 24 hours of reconstitution

HELPFUL REFERENCES

Sulbactam-durlobactam (Xacduro) Package Insert

FDA Approves New Treatment for Pneumonia Caused by Certain Difficult-to-Treat Bacteria – FDA News Release

Entasis news release for FDA Acceptance and Priority review for sulbactam-durlobactam

Efficacy and safety of sulbactam–durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii–calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK)

Study to Evaluate the Efficacy and Safety of Intravenous Sulbactam-ETX2514 in the Treatment of Patients With Infections Caused by Acinetobacter Baumannii-calcoaceticus Complex (ATTACK) – Clinical Trials.Gov

Sulbactam-durlobactam: A Step Forward in Treating Carbapenem-Resistant Acinetobacter baumannii (CRAB) Infections

Sulbactam-durlobactam: A Novel β-lactam-β-lactamase Inhibitor Combination Targeting Carbapenem-Resistant Acinetobacter baumannii Infections

Entasis listing of durlobactam publications

Entasis listing of durlobactam presentations

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