Aztreonam and Avibactam Sodium (Monograph)

Brand name: Emblaveo
Drug class: Monobactams

Introduction

Aztreonam and avibactam sodium (aztreonam/avibactam) is a fixed combination of aztreonam (a monobactam β-lactam antibiotic) and avibactam (a non--lactam -lactamase inhibitor).

Uses for Aztreonam and Avibactam Sodium

Aztreonam and avibactam has the following uses:

Aztreonam/avibactam is used in combination with metronidazole for the treatment of complicated intra-abdominal infections (cIAI) including those caused by the following susceptible gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae complex, Citrobacter freundii complex, and Serratia marcescens in patients 18 years of age and older who have limited or no alternative options. Approval of this indication is based on limited clinical safety and efficacy data for aztreonam/avibactam.

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

Aztreonam and Avibactam Sodium Dosage and Administration

General

Aztreonam and avibactam sodium is available in the following dosage form(s) and strength(s):

• Lyophilized powder in a single-dose vial containing 2 g (1.5 g aztreonam and 0.5 g avibactam).

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 by IV infusion, after reconstitution and further dilution. See Full Prescribing Information for additional details on preparation and administration.

Recommended dosage is based on creatinine clearance (Cl_cr), calculated using the Cockcroft-Gault formula (see Table 1). Aztreonam/avibactam is a combination product in a fixed 3:1 ratio. A single loading dose is followed by maintenance doses beginning at the next dosing interval. The dosing interval is calculated from the start of one infusion to the start of the subsequent infusion.

Both aztreonam and avibactam are hemodialyzable; thus, administer after hemodialysis on hemodialysis days.

For treatment of cIAI, administer metronidazole concurrently.

Recommended duration of treatment for cIAI is 5 to 14 days.

Cautions for Aztreonam and Avibactam Sodium

Contraindications

• Known hypersensitivity to the components of aztreonam and avibactam.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions were noted in patients treated with aztreonam and avibactam, including rash, flushing, and bronchospasm.

Prior to treatment, it should be established if the patient has a history of hypersensitivity reactions to components of aztreonam/avibactam. In case of hypersensitivity reactions, immediately discontinue aztreonam/avibactam and initiate appropriate medications and/or supportive care.

Serious Skin Disorders

Cases of toxic epidermal necrolysis have been reported in association with aztreonam (a component of aztreonam/avibactam) in patients undergoing bone marrow transplant with multiple risk factors including sepsis, radiation therapy, and other concomitantly administered drugs associated with toxic epidermal necrolysis. Discontinue aztreonam/avibactam if a serious skin reaction occurs.

Hepatic Adverse Reactions

Elevations in hepatic transaminases have been observed during treatment with aztreonam/avibactam. Monitoring of liver-related laboratory tests is recommended while on treatment, particularly in patients with baseline liver comorbidities or on concomitant hepatotoxic medications. If transaminase elevations are noted, consider discontinuing aztreonam/avibactam, if clinically indicated, and monitor the patient for resolution of any pertinent clinical and laboratory findings.

Clostridioides Difficile-associated Diarrhea

Clostridioides difficile-associated diarrhea(CDAD) has been reported for nearly all systemic antibacterial drugs, including aztreonam/avibactam, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit 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 use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

Development of Drug-resistant Bacteria

Prescribing aztreonam/avibactam in the absence of a proven or strongly suspected bacterial infection 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 data on the effects of aztreonam/avibactam use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Available data from case reports over several decades with aztreonam and over approximately a decade with avibactam have not identified a drug-associated risk of major birth defects, miscarriage or other maternal or fetal outcomes.

Developmental toxicity studies in pregnant rats and rabbits with daily doses of aztreonam revealed no evidence of embryotoxicity, fetotoxicity, or fetal malformations at doses 2.7- and 3.6-fold greater, respectively, than the maximum recommended human dose (MRHD) for adults of 6.5 g per day. In a peri/postnatal development (PPND) study in rats, no aztreonam-induced changes in any maternal, fetal, or neonatal parameters were observed at a dose 2.7-fold greater than the MRHD.

Avibactam administered to pregnant rats was not associated with fetal malformations at doses 6 times the MRHD of 2.17 g per day. In pregnant rabbits, avibactam administered in doses greater than or equal to 5 times the MRHD was associated with increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies. In a rat PPND study, there were no effects on pup growth and viability at doses up to 8 times the avibactam MRHD. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weaning pups with renal pelvic dilatation persisting into adulthood.

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 US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

Aztreonam is present in human milk at concentrations that are less than 1% of those determined in simultaneously obtained maternal serum. There are no data on the presence of avibactam in human milk. Avibactam is present in the milk of rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. There are no data on the effects of aztreonam or avibactam on the breastfed infant or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for aztreonam/avibactam and any potential adverse effects on the breast-fed infant from the combination drug or from the underlying maternal condition.

Pediatric Use

The safety and effectiveness of aztreonam and avibactam in pediatric patients less than 18 years of age have not been established.

Geriatric Use

In the clinical development program for aztreonam/avibactam, there were 103 patients in the aztreonam/avibactam treatment arm who were 65 years of age and older. Of these patients, 60 (58%) were between 65-74 years of age and 43 (42%) patients were 75 years of age and older. In comparison, there were 202 patients in the aztreonam/avibactam treatment arm less than 65 years of age. Clinical studies of aztreonam/avibactam did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Aztreonam and avibactam are known to be substantially excreted by the kidney, and the risk of adverse reactions to aztreonam/avibactam may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required in elderly patients based on age; the dose should be selected based on renal function).

Renal Impairment

Aztreonam and avibactam are primarily renally excreted. Plasma exposures of both aztreonam and avibactam increase with decreasing renal function, therefore dosage adjustments are recommended for aztreonam/avibactam to compensate for the slower rate of renal clearance in patients with CLcr less than 50 mL/min).

Monitor creatinine clearance in patients with changing renal function and adjust the dose of aztreonam and avibactam accordingly. Both aztreonam and avibactam are hemodialyzable; thus, aztreonam/avibactam should be administered after hemodialysis on hemodialysis days.

Common Adverse Effects

The most common adverse reactions occurring at an incidence of greater than 5% were hepatic adverse reactions, anemia, diarrhea, hypokalemia, and pyrexia.

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:

Please see product labeling for drug interaction information.

Actions and Spectrum

Mechanism of Action

Aztreonam/avibactam is a fixed combination of aztreonam (a monobactam -lactam antibiotic) and avibactam (a non--lactam -lactamase inhibitor). Aztreonam inhibits bacterial peptidoglycan cell wall synthesis following binding to penicillin binding proteins (PBPs), which leads to bacterial cell lysis and death and is stable to class B beta-lactamase enzymes (metallo-beta-lactamases). Avibactam acts by forming a covalent adduct with the enzyme that is stable to hydrolysis. Avibactam inhibits both Ambler class A, class C and some class D beta-lactamases, including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemase (KPC), OXA-48 carbapenemases, and AmpC enzymes. Avibactam does not inhibit class B enzymes and is not able to inhibit some class D enzymes.

Aztreonam/avibactam demonstrated in vitroactivity against Enterobacterales isolates expressing beta-lactamases included in Ambler Class A (CTX-M-, TEM-, and SHV-type ESBLs; KPC carbapenemase), Class B (New Delhi metallo-beta-lactamases [NDM], Verona integron-encoded metallo-beta-lactamase [VIM], and imipenemases [IMP]), Class C (AmpC), and Class D (OXA-48-like).

Resistance mechanisms to aztreonam/avibactam include beta-lactamase enzymes refractory to inhibition by avibactam and able to hydrolyze aztreonam, mutant or acquired PBPs, decreased outer membrane permeability, and active efflux pumps.

No antagonism was demonstrated in in vitro studies between aztreonam/avibactam and amikacin, ciprofloxacin, colistin, daptomycin, gentamicin, levofloxacin, linezolid, metronidazole, tigecycline, tobramycin, and vancomycin against Enterobacterales.

Avibactam restored the activity of aztreonam in animal models of infection (e.g., mouse thigh infection, mouse lung infection) caused by aztreonam non-susceptible NDM- and ESBL-producingE. coliand K. pneumoniaeisolates. However, the clinical significance of these findings is unknown.

Aztreonam/avibactam has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections: Citrobacter freundii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Klebsiella oxytoca, and Serratia marcescens.

At least 90 percent of the following bacteria exhibit an in vitroMIC less than or equal to the susceptible breakpoint for aztreonam and avibactam against isolates of similar genus or organism group; however, the safety and effectiveness of aztreonam/avibactam in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials: Citrobacter koseri, Enterobacter spp., Klebsiella aerogenes, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Raoultella ornithinolytica, Serratia spp., and Stenotrophomonas maltophilia.

Advice to Patients

• Advise patients, their families, or caregivers that allergic reactions, including serious allergic reactions, could occur that require immediate treatment. Ask them about any previous hypersensitivity reactions to aztreonam/avibactam, other beta-lactams, or other allergens.

• Advise patients about the signs and symptoms of serious skin manifestations such as sudden onset of a severe rash or blistering or peeling skin, possibly accompanied by a high fever or joint pain (these may be signs of more serious medical conditions such as toxic epidermal necrolysis).

• Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs. 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 his or her healthcare provider.

• Patients should be counseled that antibacterial drugs including aztreonam/avibactam should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When aztreonam/avibactam is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by aztreonam/avibactam or other antibacterial drugs in the future.

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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