Sulbactam (Xacduro) (sulbactam sodium)

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Administer sulbactam/durlobactam by IV infusion.

The combination therapy is available as a co-packaged kit containing 1 clear single-dose vial of sulbactam for injection 1 g (as a white to off-white powder) and 2 amber single-dose vials of durlobactam for injection 0.5 g (as a solid cake or powder). The sterile powders for injection must be reconstituted and further diluted prior to IV infusion.

Store vials of sulbactam/durlobactam refrigerated at 2 to 8degreesC (brief excursions permitted between 8 to 15degreesC). Vials should not be frozen.

Sulbactam/durlobactam is compatible with 0.9% sodium chloride. Compatibility of sulbactam/durlobactam for administration with other diluents or solutions containing other drugs has not been established. Do not mix with other drugs or solutions containing other drugs.

No in vitro studies with cytochrome P-450 (CYP) isoenzymes and sulbactam have been conducted.

In vitro studies indicate that durlobactam does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. Durlobactam is not expected to induce CYP1A2, CYP2B6, or CYP3A4.

In vitro studies indicate that sulbactam does not inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptides 1B1 (OATP1B1), OATP1B3, organic cation transporter 1 (OCT1), OCT2, bile salt export pump (BSEP), organic anion transporter 1 (OAT1), OAT3, multidrug toxin extrusion protein 1 (MATE1), or MATE2-K.

In vitro studies indicate that durlobactam does not inhibit P-gp, BCRP, OATP1B1, OAT1, OAT3, or OCT2.

Sulbactam and durlobactam are both substrates of OAT1. However, only sulbactam is predicted to have active secretion as a significant portion of total clearance; therefore, inhibition of OAT1 may increase sulbactam plasma concentrations.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

*History of known hypersensitivity to sulbactam, durlobactam, or other beta-lactam antibacterial drugs.

There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min

There are no moderate contraindications for this drug.

The most common adverse reactions (incidence >10%) reported with sulbactam/durlobactam in clinical studies were liver test abnormalities, diarrhea, anemia, and hypokalemia.

More Frequent

• Abnormal hepatic function tests
• Anemia
• Hypokalemia

Less Frequent

• Cardiac arrhythmia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Thrombocytopenic disorder

Rare or Very Rare

• Clostridioides difficile infection
• Hypersensitivity drug reaction

More Frequent

• Diarrhea

Less Frequent

• Constipation

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Safety and efficacy of sulbactam/durlobactam have not been established in pediatric patients.

There are no available data on sulbactam/durlobactam use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

There are case reports and case series describing sulbactam use (in combination with ampicillin) in pregnancy; no drug-associated risk or adverse maternal or fetal outcomes have been reported. Studies show that sulbactam does cross the placenta. In animal studies, doses up to 10 times the human dose have not demonstrated evidence of harm to the fetus.

There are no available data on durlobactam use in pregnant women. In animal studies, no drug-induced fetal malformations were observed, but an increased incidence of fetal skeletal variations was observed when durlobactam was administered during organogenesis at 2- and 4- times the Maximum Recommended Human Dose.

Sulbactam is present in human milk in low concentrations; a maximum daily infant dose of 560 mcg/kg/day, assuming mean milk consumption of 200 mL/kg/day, has been reported. It is not known whether durlobactam is distributed into human milk. Effects of sulbactam, durlobactam, or the combination of sulbactam/durlobactam on breast-fed infants or milk production are not known.

Because of the greater frequency of reduced renal function in geriatric patients, care should be taken with dosing, and dosage should be adjusted based on renal function.

In the ATTACK trial, 54% of sulbactam/durlobactam-treated patients were >=65 years of age, and 19% of patients were >=76 years of age. There were not enough patients >=65 years of age to determine whether they respond differently than younger patients; however, sulbactam/durlobactam is renally excreted, and because geriatric patients are more likely to have decreased renal function, changes in renal function should be closely monitored.