Sulbactam and Durlobactam (Monograph)

Brand name: Xacduro
Drug class: Other Miscellaneous Antibacterials

Introduction

Sulbactam sodium and durlobactam sodium is a combination preparation containing sulbactam sodium, a penicillin derivative beta-lactam antibacterial and beta-lactamase inhibitor, and durlobactam sodium, a diazabicyclooctane beta-lactamase inhibitor.

Uses for Sulbactam and Durlobactam

Sulbactam sodium and durlobactam sodium has the following uses:

Sulbactam sodium and durlobactam sodium (sulbactam/durlobactam) is indicated in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex.

Sulbactam/durlobactam is not indicated for the treatment of HABP/VABP caused by pathogens other than susceptible isolates of Acinetobacter baumannii-calcoaceticus complex.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulbactam/durlobactam and other antibacterial drugs, sulbactam/durlobactam should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Sulbactam and Durlobactam Dosage and Administration

General

Sulbactam sodium and durlobactam sodium (sulbactam/durlobactam) is available in the following dosage form(s) and strength(s):

A co-packaged kit containing the following two components as sterile powders for reconstitution and further dilution prior to IV infusion:

• 1 clear single-dose vial of sulbactam for injection 1 g

• 2 amber single-dose vials of durlobactam for injection 0.5 g

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Administer sulbactam/durlobactam (1 g of sulbactam, 1 g of durlobactam) every 6 hours by IV infusion over 3 hours in patients with creatinine clearance (CL_cr) of 45 to 129 mL/minute.

• Dosing regimen adjustments are recommended for CL_cr less than 45 mL/minute and CL_cr greater than or equal to 130 mL/minute. See full prescribing information for dosage adjustment recommendations.

• The recommended duration of treatment is 7 to 14 days. The duration of therapy should be guided by the patient's clinical status.

• Administer all doses of sulbactam/durlobactam by IV infusion over 3 hours.

• See full prescribing information for instructions on the preparation of the IV solution.

Related/similar drugs

durlobactam / sulbactam

Cautions for Sulbactam and Durlobactam

Contraindications

• Known history of severe hypersensitivity to the components of sulbactam sodium and durlobactam sodium (sulbactam/durlobactam), or other beta-lactam antibacterial drugs.

Warnings/Precautions

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. Hypersensitivity was observed in patients treated with sulbactam/durlobactam in clinical trials. Before initiating therapy with sulbactam/durlobactam, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta lactams, and other allergens. Discontinue sulbactam/durlobactam if an allergic reaction occurs.

Clostridioides Difficile-associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulbactam/durlobactam, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, the risk/benefit of continuing treatment with sulbactam/durlobactam should be assessed. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development of Drug-resistant Bacteria

Prescribing sulbactam/durlobactam in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Specific Populations

Pregnancy

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

Sulbactam: Available published data from case reports and case series with sulbactam use in combination with ampicillin during pregnancy over many decades have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. The published literature reports that sulbactam crosses the human placenta. Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten (10) times the human dose and have revealed no evidence of harm to the fetus due to sulbactam.

Durlobactam: There are no available data on the use of durlobactam in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Durlobactam administered to pregnant mice and rats during organogenesis showed no drug-induced fetal malformations but an increased incidence of skeletal variations was observed in mice at 2- and 4-times the Maximum Recommended Human Dose (MRHD).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of durlobactam in human or animal milk. Sulbactam is present in human milk in low concentrations. Published data report sulbactam in breastmilk at an estimated maximum daily infant dose of 560 mcg/kg/day (1% to 2% of adult weight-adjusted dose), assuming mean milk consumption of 200 mL/kg/day. There are no data on the effects of sulbactam/durlobactam, sulbactam, or durlobactam on the breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sulbactam/durlobactam and any potential adverse effects on the breastfed child from the combination therapy or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of sulbactam/durlobactam in pediatric patients younger than 18 years of age have not been established.

Geriatric Use

Of the 91 patients treated with sulbactam/durlobactam in the principal efficacy study, 49 (54%) were 65 years of age and older, including 17 (19%) patients 76 years of age and older. Clinical studies of sulbactam/durlobactam did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently than younger patients.

Sulbactam/durlobactam is known to be substantially excreted by the kidney and elderly patients are more likely to have decreased renal function. Adjust dosing regimen for elderly patients based on renal function.

Renal Impairment

No dosage adjustment of sulbactam/durlobactam is recommended in patients with CL_cr of 45 to 129 mL/minute.

Adjustments to the sulbactam/durlobactam dosing regimen are required in patients with CL_cr less than 45 mL/minute. In patients requiring hemodialysis, complete the procedure at the latest possible time before the start of sulbactam/durlobactam dosing. Monitor renal function regularly and adjust the dosage of sulbactam/durlobactam accordingly as renal function may change during the course of therapy.

Limited information is available to provide a dosage recommendation in the setting of continuous renal replacement therapy (CRRT) and therapy should be guided by the patient's clinical status. While on CRRT, a patient's residual renal function may change, which may warrant a change in sulbactam/durlobactam dosage. Monitor renal function regularly and adjust the dosage of sulbactam/durlobactam accordingly as renal function may change during the course of therapy.

CL_cr of 130 mL/minute or greater may be seen in seriously ill patients who are receiving IV fluid resuscitation. Dosage adjustment of sulbactam/durlobactam is required in patients with CL_cr of 130 mL/minute or greater. Monitor renal function regularly and adjust the dosage of sulbactam/durlobactam accordingly as renal function may change during the course of therapy.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of sulbactam/durlobactam have not been evaluated. Hepatic impairment is not expected to alter the elimination of sulbactam/durlobactam as neither sulbactam nor durlobactam undergo substantial hepatic metabolism/excretion. Dosage adjustments are not necessary in patients with impaired hepatic function.

Common Adverse Effects

The most common adverse reactions (incidence >10%) were liver test abnormalities, diarrhea, anemia, and hypokalemia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Organic Anion Transporter 1 (OAT1) Inhibitors: Concomitant administration with OAT1 inhibitors may increase plasma concentrations of sulbactam/durlobactam. Concomitant administration is not recommended.

Actions and Spectrum

Mechanism of Action

Sulbactam sodium and durlobactam sodium (sulbactam/durlobactam) is a co-packaged product containing sulbactam and durlobactam. Sulbactam is a beta-lactam antibacterial and Ambler Class A serine beta-lactamase inhibitor that has bactericidal activity due to its inhibition of Acinetobacter baumannii-calcoaceticus complex (ABC) penicillin-binding proteins PBP1 and PBP3, which are essential enzymes required for bacterial cell wall synthesis.

Durlobactam is a diazabicyclooctane non-beta-lactam, beta-lactamase inhibitor, that protects sulbactam from degradation by certain serine-beta-lactamases. Durlobactam alone does not have antibacterial activity against ABC isolates.

Sulbactam/durlobactam demonstrated in vitro activity against ABC isolates expressing serine beta-lactamases included in Ambler Class A (CTX-M-, TEM-, PER- and SHV-type extended spectrum beta-lactamases [ESBLs], KPC carbapenemase) Class C (ADC-type) and broad spectrum activity against Class D (OXA-type) enzymes.

Spectrum

Sulbactam sodium and durlobactam sodium (sulbactam/durlobactam) has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections: Acinetobacter baumannii-calcoaceticus complex.

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for sulbactam/durlobactam, please see: https://www.fda.gov/STIC.

Resistance

Mechanisms of beta-lactam resistance in ABC isolates may include either the production of beta-lactamases, modification of PBPs or target alteration, up-regulation of efflux pumps or loss of outer membrane porin.

Sulbactam/durlobactam is not active against ABC isolates that produce Ambler Class B metallo-beta-lactamases or have modification of active target site of sulbactam (i.e., PBPs). Isolates may also produce in combination multiple beta-lactamases, express varying levels of beta-lactamases, have amino acid PBPs sequence variations or other resistance mechanisms that may contribute to resistance.

Advice to Patients

• Advise the patient, their families, or caregivers that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask them about any previous hypersensitivity reactions to sulbactam sodium and durlobactam sodium (sulbactam and durlobactam), other beta-lactams (including cephalosporins), or other allergens.

• Advise the patient, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including sulbactam/durlobactam. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell them to contact their healthcare provider.

• Patients should be counseled that antibacterial drugs, including sulbactam/durlobactam, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). Patients should be told that the medication should be administered exactly as directed.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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