Introduction
Xacduro (sulbactam-durlobactam) is a novel antibacterial combination therapy approved by the FDA in 2023 for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) caused by susceptible strains of Acinetobacter baumannii-calcoaceticus complex. This fixed-dose combination represents a significant advancement in addressing the growing challenge of carbapenem-resistant Acinetobacter infections, which have limited treatment options and high mortality rates.
Mechanism of Action
Xacduro combines sulbactam, a beta-lactam antibiotic with intrinsic activity against Acinetobacter species, and durlobactam, a novel beta-lactamase inhibitor. Sulbactam exhibits bactericidal activity by binding to penicillin-binding proteins (PBPs), particularly PBP2 in Acinetobacter species, inhibiting bacterial cell wall synthesis. Durlobactam protects sulbactam from degradation by inhibiting Ambler class A, C, and D beta-lactamases, including carbapenemases such as OXA-type enzymes commonly produced by carbapenem-resistant Acinetobacter baumannii.
Indications
Xacduro is indicated for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex in patients 18 years of age and older.
Dosage and Administration
Standard dosing: 1 g sulbactam/1 g durlobactam administered by intravenous infusion over 3 hours every 6 hours Duration of therapy: 7-14 days, depending on clinical response Preparation: Reconstitute with sterile water for injection and further dilute in 0.9% sodium chloride injection to a final concentration of 10 mg/mL sulbactam/10 mg/mL durlobactam Special populations:- Renal impairment: No dosage adjustment required for mild to moderate impairment (eGFR ≥30 mL/min/1.73m²). Not recommended for severe renal impairment (eGFR <30 mL/min/1.73m²)
- Hepatic impairment: No dosage adjustment required
- Elderly: No dosage adjustment required based on age alone
Pharmacokinetics
Absorption: Administered intravenously only; complete bioavailability Distribution: Steady-state volume of distribution approximately 20-30 L for both components. Both drugs distribute into lung epithelial lining fluid at concentrations exceeding plasma concentrations Metabolism: Minimal metabolism; both components are primarily eliminated unchanged Elimination: Primarily renal excretion with half-life of approximately 1.5-2 hours for both components. Approximately 75-85% of administered dose recovered unchanged in urine Protein binding: Sulbactam: 38%; Durlobactam: 9%Contraindications
- History of severe hypersensitivity reactions (e.g., anaphylaxis) to sulbactam, durlobactam, or other beta-lactam antibacterial drugs
Warnings and Precautions
Hypersensitivity reactions: Serious and occasionally fatal hypersensitivity reactions have been reported with beta-lactam antibiotics. Discontinue Xacduro if allergic reaction occurs Clostridium difficile-associated diarrhea: May range from mild diarrhea to fatal colitis. Evaluate if diarrhea occurs Development of drug-resistant bacteria: Prescribe only for proven or strongly suspected bacterial infections. Misuse may lead to development of resistant organisms Risk in patients with renal impairment: Use with caution in patients with severe renal impairment (eGFR <30 mL/min/1.73m²)Drug Interactions
Probenecid: Co-administration may decrease renal clearance of sulbactam and durlobactam, potentially increasing systemic exposure Other nephrotoxic drugs: Use with caution when administering concurrently with other potentially nephrotoxic drugs Warfarin: Monitor coagulation parameters closely when co-administering with warfarin due to potential effects on vitamin K-dependent clotting factorsAdverse Effects
Most common adverse reactions (≥10%):- Liver function test abnormalities (increased ALT, AST)
- Anemia
- Hypokalemia
- Renal impairment
- Hypersensitivity reactions
- Clostridium difficile-associated diarrhea
- Neurological adverse reactions (reported with other beta-lactams)
Monitoring Parameters
- Clinical response: Temperature, white blood cell count, oxygenation, radiographic findings
- Renal function: Serum creatinine at baseline and periodically during treatment
- Liver function: ALT, AST at baseline and periodically
- Complete blood count: Monitor for anemia and other hematological abnormalities
- Electrolytes: Particularly potassium levels
- Signs of hypersensitivity reactions
- Signs of C. difficile-associated diarrhea
Patient Education
- Complete the full course of therapy even if feeling better
- Report any signs of allergic reaction (rash, itching, swelling, difficulty breathing)
- Report severe diarrhea, abdominal pain, or bloody stools during or after treatment
- Inform healthcare providers of all medications being taken
- Notify healthcare provider if pregnant, planning pregnancy, or breastfeeding
- Understand that this medication is specifically for serious hospital-acquired infections
References
1. FDA Approval Package: Xacduro (sulbactam-durlobactam). May 2023 2. Kaye KS, et al. 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 Trial. Lancet Infect Dis. 2023;23(9):1072-1084 3. McLeod SM, et al. Discovery of Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter baumannii Infections. ACS Infect Dis. 2021;7(5):1124-1132 4. Xacduro [package insert]. Waltham, MA: Entasis Therapeutics Inc.; 2023 5. World Health Organization. Guidelines for the Prevention and Control of Carbapenem-Resistant Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa in Health Care Facilities. Geneva: WHO; 2017