Sulbactam-durlobactam photo pending
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
- Durlobactam can inhibit class A, C, and D beta-lactamases. This includes CTX-M, KPC, SHV, TEM, ADC-type, and OXA-type enzymes.
- 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)
- 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 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
- 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
- The pharmacokinetic-pharmacodynamic paramater for sulbactam is time above MIC and for durlobactam is 24-hour unbound AUC
- 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
Entasis news release for FDA Acceptance and Priority review for sulbactam-durlobactam
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