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Meropenem and Vaborbactam

Pronunciation

(mer oh PEN em & va bor BAK tam)

Index Terms

  • Vaborbactam and Meropenem

Dosage Forms

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

Solution Reconstituted, Intravenous:

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

Brand Names: U.S.

  • Vabomere

Pharmacologic Category

  • Antibiotic, Carbapenem
  • Beta-Lactamase Inhibitor

Pharmacology

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.

Distribution

Vd: 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%

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

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.

Dosing: Renal Impairment

Note: Estimation of renal function for the purpose of drug dosing should be done using the Modification of Diet in Renal Disease (MDRD) formula. Dosage recommendations are expressed as grams of meropenem/vaborbactam combination.

eGFR ≥50 mL/minute/1.73 m2: No dosage adjustment necessary

eGFR 30 to 49 mL/minute/1.73 m2: 2 g every 8 hours

eGFR 15 to 29 mL/minute/1.73 m2: 2 g every 12 hours

eGFR <15 mL/minute/1.73 m2: 1 g every 12 hours

Hemodialysis patients: Dialyzable (meropenem: 38%; vaborbactam: 53%): Adjust dose based on degree of renal impairment; administer dose after hemodialysis on dialysis days.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling. However, dosage adjustment unlikely because hepatic disease does not affect pharmacokinetics of meropenem and vaborbactam does not undergo hepatic elimination.

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 of meropenem and vaborbactam will be ~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. 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: 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 Considerations

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

Also refer to the meropenem monograph for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, injection site irritation, or diarrhea. Have patient report immediately to prescriber seizures, muscle rigidity, tremors, abnormal movements, burning or numbness feeling, confusion, or signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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