Meropenem and Vaborbactam

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Vabomere: 2 g: Meropenem 1 g and vaborbactam 1 g (1 ea)

Pharmacology

Mechanism of Action

Meropenem: Inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins, which in turn inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis; bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested

Vaborbactam is a beta-lactamase inhibitor that protects meropenem from degradation by certain serine beta-lactamases (eg, K. pneumonia carbapenemase [KPC]). Vaborbactam does not have antibacterial activity.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: Meropenem: 20.2 L; Vaborbactam: 18.6 L

Metabolism

Meropenem: Hydrolysis of beta-lactam bond to open lactam form (minor); Vaborbactam: Not metabolized

Excretion

Meropenem: Urine (40% to 60% [unchanged]; 22% inactive hydrolysis product); feces (~2%); Vaborbactam: Urine (75% to 95% [unchanged])

Half-Life Elimination

Meropenem: 1.22 hours; Vaborbactam: 1.68 hours

Protein Binding

Meropenem: ~2%; Vaborbactam: ~33%

Use in Specific Populations

Special Populations: Renal Function Impairment

Meropenem AUC ratios to subjects with normal renal function are 1.28, 2.07, and 4.63 for subjects with mild (eGFR 60 to 89 mL/minute/1.73 m²), moderate (eGFR 30 to 59 mL/minute/1.73 m²), and severe (eGFR <30 mL/minute/1.73 m²) renal impairment, respectively. Vaborbactam AUC ratios to subjects with normal renal function are 1.18, 2.31, and 7.8 for subjects with mild, moderate, and severe renal impairment, respectively. Vaborbactam exposure was high in subjects with end-stage renal disease and higher when administered after dialysis than when administered before.

Use: Labeled Indications

Urinary tract infections, complicated: Treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by susceptible Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex in patients ≥18 years of age

Contraindications

Hypersensitivity to meropenem, vaborbactam, other carbapenems or beta-lactamase inhibitors, or any component of the formulation; patients who have demonstrated anaphylactic reactions to beta-lactam antibacterial agents

Dosage and Administration

Dosing: Adult

Note: Dosage recommendations are expressed as grams of meropenem/vaborbactam combination.

Urinary tract infections, complicated (including pyelonephritis): IV: 4 g every 8 hours for ≤14 days

Dosing: Geriatric

Refer to adult dosing.

Reconstitution

Each vial should be reconstituted with 20 mL of NS that is withdrawn from the infusion bag. Mix gently to dissolve (concentration of meropenem ~0.05 g/mL and vaborbactam ~0.05 g/mL; final vial volume ~21.3 mL). Reconstituted solution should be additionally diluted in NS immediately by adding it back into the infusion bag (70 to 250 mL infusion bag for 1 g [meropenem 0.5 g and vaborbactam 0.5 g] dose; 125 to 500 mL infusion bag for 2 g [meropenem 1 g and vaborbactam 1 g] dose; 250 to 1,000 mL for 4 g dose [meropenem 2 g and vaborbactam 2 g]). Final concentration: meropenem (~2 to 8 mg/mL) and vaborbactam (~2 to 8 mg/mL).

Administration

IV: Administer by IV infusion over 3 hours.

Dietary Considerations

Some products may contain sodium.

Storage

Store intact vials at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F). Diluted solution for infusion is stable for 4 hours at room temperature or 22 hours when stored at 2°C to 8°C (36°F to 46°F).

Drug Interactions

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Avoid combination

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Probenecid: May increase the serum concentration of Meropenem. Avoid combination

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Valproate Products: Carbapenems may decrease the serum concentration of Valproate Products. Management: Concurrent use of carbapenem antibiotics with valproic acid is generally not recommended. Alternative antimicrobial agents should be considered, but if a concurrent carbapenem is necessary, consider additional anti-seizure medication. Consider therapy modification

Test Interactions

Positive Coombs'

Adverse Reactions

Note: Reactions may not be exclusive to meropenem and vaborbactam. Some patients in this study were switched to levofloxacin after 15 doses of meropenem and vaborbactam.

Also see Meropenem.

1% to 10%:

Cardiovascular: Phlebitis (≤4%)

Central nervous system: Headache (9%)

Endocrine & metabolic: Hypokalemia (1%)

Gastrointestinal: Diarrhea (3%), nausea (2%)

Hepatic: Increased serum ALT (2%), increased serum AST (2%)

Hypersensitivity: Hypersensitivity (2%)

Local: Infusion site reaction (≤4%)

Miscellaneous: Fever (2%)

Frequency not defined: Gastrointestinal: Clostridioides (formerly Clostridium) difficile-associated diarrhea

<1%, postmarketing, and/or case reports: Azotemia, chest discomfort, decreased appetite, deep vein thrombosis, dizziness, hallucination, hyperglycemia, hyperkalemia, hypoglycemia, hypotension, increased creatine phosphokinase, insomnia, lethargy, leukopenia, oral candidiasis, paresthesia, pharyngitis, renal impairment, tremor, vulvovaginal candidiasis

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylaxis and serious skin reactions, have been reported with beta-lactam antibacterial agents. Risk may be increased in patients with history of sensitivity to multiple allergens; inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactam antibacterials, and other allergens prior to treatment initiation. Discontinue use if an allergic reaction occurs.
• CNS effects: Associated with CNS adverse effects, including seizures; use with caution in patients with CNS disorders (eg, brain lesions, history of seizures) or with bacterial meningitis and/or compromised renal function. Closely adhere to recommended dosing, especially in patients with risk factors for seizures. Patients who develop focal tremors, myoclonus, or seizures should undergo neurological evaluation and may require dosage adjustment or discontinuation of treatment. Outpatient use may result in paresthesias, seizures, delirium and/or headaches that can impair neuromotor function and alertness; patients should not operate machinery or drive until it is established that meropenem and vaborbactam is well tolerated.
• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required in patients with creatinine clearance <50 mL/minute. Increased seizure risk and thrombocytopenia have been reported in patients with renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Monitor for signs of hypersensitivity reaction, including anaphylaxis and serious skin reactions. Periodically monitor renal function; in patients with changing renal function, monitor serum creatinine and eGFR at least daily.

Pregnancy

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination; adverse events were observed in animal reproduction studies following administration of the vaborbactam component.

Also refer to the meropenem monograph for additional information.

Patient Education

What is this drug used for?

• It is used to treat a urinary tract infection (UTI).

Frequently reported side effects of this drug

• Headache
• Injection site irritation
• Diarrhea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Seizures
• Stiff muscles
• Tremors
• Abnormal movements
• Burning or numbness feeling
• Confusion
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Clostridium difficile (C. diff)-associated diarrhea like abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.