CLASSES

Carbapenem and Beta-Lactamase Inhibitor Combination Antibiotics

DEA CLASS

Rx

DESCRIPTION

Combination of meropenem, a carbapenem antibacterial, and vaborbactam, a beta-lactamase inhibitor
Used for complicated urinary tract infections (cUTIs) including pyelonephritis in adults caused by susceptible E. coli, K. pneumoniae, and E. cloacae
Activity against meropenem-resistant organisms, including KPC-producing Enterobacteriaceae

COMMON BRAND NAMES

VABOMERE

HOW SUPPLIED

VABOMERE Intravenous Inj Pwd: 1-1g

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

12 g/day (6 g meropenem and 6 g vaborbactam) IV.

12 g/day (6 g meropenem and 6 g vaborbactam) IV.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Meropenem pharmacokinetics are not affected by hepatic impairment and vaborbactam does not undergo hepatic metabolism.

Renal dosing is based on estimated glomerular filtration rate (eGFR) as calculated by the MDRD equation:
eGFR 50 mL/minute/1.73 m2 or more: No dosage adjustment needed.
eGFR 30 to 49 mL/minute/1.73 m2: 2 g (1 g meropenem and 1 g vaborbactam) every 8 hours.
eGFR 15 to 29 mL/minute/1.73 m2: 2 g (1 g meropenem and 1 g vaborbactam) every 12 hours.
eGFR less than 15 mL/minute/1.73 m2: 1 g (0.5 g meropenem and 0.5 g vaborbactam) every 12 hours.
 
Intermittent hemodialysis
Meropenem and vaborbactam are removed by hemodialysis. For patients maintained on hemodialysis, administer meropenem; vaborbactam after the hemodialysis session.

ADMINISTRATION

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

STORAGE

VABOMERE:
- Discard unused portion. Do not store for later use.
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
- Store diluted product in accordance with package insert instructions

CONTRAINDICATIONS / PRECAUTIONS

Positive Coombs' tests have been reported in patients receiving meropenem; vaborbactam. In patients receiving meropenem; vaborbactam and undergoing hematologic testing, a positive Coombs' test should be considered as possibly being caused by the antibiotic.
 
A false-positive reaction for glucose in the urine has been observed in patients receiving beta-lactam antibiotics, including carbapenems, and using copper-reduction tests (e.g., Benedict's solution, Fehling's solution, and Clinitest tablets). This reaction, however, has not been observed with glucose oxidase tests (e.g., Tes-tape, Clinistix, Diastix).

Meropenem; vaborbactam is contraindicated in patients with known meropenem hypersensitivity, vaborbactam hypersensitivity, carbapenem hypersensitivity, or a previous anaphylactic reaction to beta-lactams. Serious and occasionally fatal hypersensitivity reactions have been reported in patients receiving therapy with beta-lactams and are more likely to occur in persons with a history of sensitivity to multiple allergens. There have been reports of patients with a history of penicillin hypersensitivity that have experienced a severe hypersensitivity reaction when treated with another beta-lactam antibiotic. Before starting meropenem; vaborbactam therapy, inquire about previous penicillin hypersensitivity, cephalosporin hypersensitivity, other beta-lactam antibiotic hypersensitivity, and other allergens. If an allergic reaction to meropenem; vaborbactam occurs, discontinue the drug immediately.

Use meropenem; vaborbactam cautiously in patients with brain lesions, a history of seizure disorder, or other neurological disease or condition that may lower the seizure threshold, such as head trauma or bacterial meningitis. Seizures have been reported with meropenem use and have occurred most commonly in patients with these types of conditions; however, the risk of seizures appears to be low and is thought to be less than the risk associated with imipenem; cilastatin. The risk of seizures increases in patients given meropenem; vaborbactam doses higher than recommended (e.g., patients with compromised renal function) or patients receiving concomitant medications with seizure potential. Adhere to recommended dosage ranges, especially in patients with known factors that predispose to convulsive activity. Continue anti-convulsant therapy in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically; place on anti-convulsant therapy if not already receiving, and reconsider the meropenem; vaborbactam dosage for dosage reduction or discontinuation.

Use meropenem; vaborbactam cautiously in patients with renal impairment or renal failure because both agents are primarily eliminated by the kidneys. These patients are at higher risk for developing seizures while receiving meropenem; vaborbactam. Thrombocytopenia has also been reported in patients with renal function impairment, although clinical bleeding has not been reported. Dosage adjustments are required in patients with renal impairment. For patients with changing renal function, monitor serum creatinine and estimated glomerular filtration rate (eGFR) at least daily and adjust the meropenem; vaborbactam dosage as necessary.

Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including meropenem; vaborbactam, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Neuromotor impairment, including seizures, delirium, headache, and/or paresthesias may occur in patients receiving meropenem; vaborbactam. Patients should avoid driving or operating machinery until drug tolerability has been established.

No overall differences in safety or effectiveness of meropenem; vaborbactam were observed between geriatric subjects and younger adult subjects in clinical trials; spontaneous reports and other reported clinical experience have not identified differences in responses. Meropenem and vaborbactam are substantially excreted by the kidney and the risk of adverse reactions may be greater in those with renal impairment. Because geriatric 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. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem; vaborbactam in pregnancy. Fetal malformations, including supernumerary lung lobes and interventricular septal defect, were observed in offspring from pregnant rabbits given intravenous vaborbactam during organogenesis at doses approximately equal to or above the maximum recommended human dose (MRHD) based on plasma AUC comparison. No fetal toxicity or malformations have been demonstrated in animal studies with intravenous meropenem use during organogenesis at doses up to 1.6 times the MRHD based on body surface area. Advise pregnant women of the potential risks to the fetus.

Meropenem is excreted in human breast milk. It is unknown whether vaborbactam is excreted in human breast milk. No data are available on the effects of meropenem and vaborbactam on the breast-fed child or milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for meropenem; vaborbactam and potential adverse effects on the breast-fed child from meropenem; vaborbactam or the underlying maternal condition.

ADVERSE REACTIONS

thrombosis / Delayed / 0-1.0
hyperkalemia / Delayed / 0-1.0
azotemia / Delayed / 0-1.0
hemolytic anemia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
erythema multiforme / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
seizures / Delayed / Incidence not known
C. difficile-associated diarrhea / Delayed / Incidence not known

phlebitis / Rapid / 4.4-4.4
elevated hepatic enzymes / Delayed / 1.5-1.8
hypokalemia / Delayed / 1.1-1.1
leukopenia / Delayed / 0-1.0
hypotension / Rapid / 0-1.0
candidiasis / Delayed / 0-1.0
hypoglycemia / Early / 0-1.0
hyperglycemia / Delayed / 0-1.0
hallucinations / Early / 0-1.0
eosinophilia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
thrombocytosis / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
delirium / Early / Incidence not known
superinfection / Delayed / Incidence not known
pseudomembranous colitis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known

headache / Early / 8.8-8.8
injection site reaction / Rapid / 4.4-4.4
diarrhea / Early / 3.3-3.3
nausea / Early / 1.8-1.8
fever / Early / 1.5-1.5
lethargy / Early / 0-1.0
paresthesias / Delayed / 0-1.0
dizziness / Early / 0-1.0
tremor / Early / 0-1.0
pharyngitis / Delayed / 0-1.0
insomnia / Early / 0-1.0
rash / Early / Incidence not known
pruritus / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
abdominal pain / Early / Incidence not known
infection / Delayed / Incidence not known

DRUG INTERACTIONS

Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Probenecid: (Moderate) Concurrent administration of meropenem with probenecid is not recommended as probenecid inhibits the renal excretion of meropenem by competing for active tubular secretion. After administration of probenecid with meropenem, the mean systemic exposure of meropenem increased by 56% and the half-life increased by 38%. Meropenem is a substrate of OAT1 and OAT3 transporters in the proximal tubule of the kidney, and probenecid is an inhibitor of these drug transporters.
Probenecid; Colchicine: (Moderate) Concurrent administration of meropenem with probenecid is not recommended as probenecid inhibits the renal excretion of meropenem by competing for active tubular secretion. After administration of probenecid with meropenem, the mean systemic exposure of meropenem increased by 56% and the half-life increased by 38%. Meropenem is a substrate of OAT1 and OAT3 transporters in the proximal tubule of the kidney, and probenecid is an inhibitor of these drug transporters.
Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
Valproic Acid, Divalproex Sodium: (Major) Avoid concomitant carbapenem and valproic acid use. Consider alternative antibacterial therapies other than carbapenems to treat infections in patients whose seizures are well controlled with valproic acid or divalproex sodium. If coadministered, monitor valproic acid concentrations. Coadministration of carbapenems with valproic acid or divalproex sodium may reduce the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. Carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing valproic acid serum concentrations.
Warfarin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.

PREGNANCY AND LACTATION

There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem; vaborbactam in pregnancy. Fetal malformations, including supernumerary lung lobes and interventricular septal defect, were observed in offspring from pregnant rabbits given intravenous vaborbactam during organogenesis at doses approximately equal to or above the maximum recommended human dose (MRHD) based on plasma AUC comparison. No fetal toxicity or malformations have been demonstrated in animal studies with intravenous meropenem use during organogenesis at doses up to 1.6 times the MRHD based on body surface area. Advise pregnant women of the potential risks to the fetus.

Meropenem is excreted in human breast milk. It is unknown whether vaborbactam is excreted in human breast milk. No data are available on the effects of meropenem and vaborbactam on the breast-fed child or milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for meropenem; vaborbactam and potential adverse effects on the breast-fed child from meropenem; vaborbactam or the underlying maternal condition.

MECHANISM OF ACTION

Meropenem, a carbapenem beta-lactam antibiotic, is mainly bactericidal. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall.[28347] [62277] PBPs are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. PBPs vary among different bacterial species. Meropenem readily penetrates the outer membrane of bacteria cells. After penetrating the bacterial cell wall, it binds to several PBPs. Meropenem has high affinity for PBP-2, PBP-3, and PBP-4 of E. coli and P. aeruginosa and PBP-1, PBP-2, and PBP-4 of S. aureus.[28347] [35440] The rapid bactericidal activity of the carbapenems against gram-negative bacteria is associated with their great affinity for PBP-1a, PBP-1b, and PBP-2, rather than PBP-3 (the primary target for other beta-lactams).[35441] There are differences in preferential binding sites between the carbapenems. Imipenem preferentially binds to PBP-2, then PBP-1a and PBP-1b, with a weak affinity for PBP-3. Meropenem and ertapenem preferentially bind to PBP-2, then PBP-3, but also have a strong affinity for PBP-1a and PBP-1b. Doripenem has a strong affinity for PBP-3 in P. aeruginosa, PBP-1, PBP-2, and PBP-4 in S. aureus, and PBP-2 in E. coli.[35441] Cell lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor. Prevention of the autolysin response to beta-lactam antibiotic exposure through loss of autolytic activity (mutation) or inactivation of autolysin (low-medium pH) by the microorganism can lead to tolerance to the beta-lactam antibiotic resulting in bacteriostatic activity.[51465]
 
Vaborbactam is a non-suicidal beta-lactamase inhibitor that protects meropenem from degradation by certain serine beta-lactamases, such as Klebsiella pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity. It does not decrease the activity of meropenem against meropenem-susceptible organisms.[62277]
 
Beta-lactams, including meropenem, exhibit concentration-independent or time-dependent killing. In vitro and in vivo animal studies have demonstrated that the major pharmacodynamic parameter that determines efficacy for beta-lactams is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism.[34145] [34143] [35436] [35437] [35438] [35439] The ratio of the 24-hour unbound plasma vaborbactam AUC to meropenem; vaborbactam MIC is the index that best predicts efficacy of vaborbactam in combination with meropenem in animal and in vitro models.[62277] This microbiological killing pattern is due to the mechanism of action, which is acylation of PBPs. There is a maximum proportion of PBPs that can be acylated; therefore, once maximum acylation has occurred, killing rates cannot increase.[35439] Free beta-lactam concentrations do not have to remain above the MIC for the entire dosing interval. The percentage of time required for both bacteriostatic and maximal bactericidal activity is different for the various classes of beta-lactams. Carbapenems require free drug concentrations to exceed the MIC for 20% of the dosing interval for bacteriostatic activity and 40% of the dosing interval for maximal bactericidal activity.[35436] [35437] [35438] Carbapenems also are reported to have a post-antibiotic effect (PAE). PAE is defined as the suppression of bacterial growth that continues after the antibiotic concentration falls below the bacterial MIC. PAE has been reported to be 4 to 5 hours with meropenem.[35441]
 
The susceptibility interpretive criteria for meropenem; vaborbactam are delineated by pathogen. The MICs are defined for Enterobacterales as susceptible at 4/8 mcg/mL or less, intermediate at 8/8 mcg/mL, and resistant at 16/8 mcg/mL or more based on a dosage of 4 g (2 g meropenem and 2 g vaborbactam) IV every 8 hours.[63320] [63321]
 
There are 4 general mechanisms of carbapenem resistance including decreased permeability of the outer membrane of gram-negative organisms due to decreased porin channel production, decreased affinity for the target PBPs, over-expression of efflux pumps, and enzymatic degradation.[28347] Generally, carbapenems show stability to the majority of beta-lactamases, including AmpC beta-lactamases and extended-spectrum beta-lactamases (ESBLs). However, specific intrinsic or acquired beta-lactamases, generally called carbapenemases, can hydrolyze the carbapenems. These include some class A enzymes, several class D (OXA) enzymes, and the class B metallo-beta-lactamases.[28347] [35440] [35441] [62277] Meropenem; vaborbactam has demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and ESBLs, including KPC, SME, TEM, SHV, CTX-M, CMY, and ACT; however, it is not active against organisms that produce metallo-beta-lactamases or oxacillinases with carbapenemase activity.[62277] A deficiency in the outer membrane porin protein (Opr) D2 is associated with decreased carbapenem susceptibility in gram-negative bacteria. However, it is theorized that a combination of resistance mechanisms is required for significant carbapenem resistance. Decreased porin OprD in combination with activity of a chromosomal AmpC beta-lactamase is associated with imipenem, doripenem, and to a lesser extent meropenem resistance. Doripenem and meropenem may also require over-expression of efflux pumps for resistance to emerge; imipenem is not subject to efflux. Theoretically, efflux activity plus loss of membrane permeability is less likely to happen in vivo than AmpC beta-lactamase expression and loss of membrane permeability.[35440] [35441] Meropenem; vaborbactam may not have activity against gram-negative bacteria that have porin mutations combined with overexpression of efflux pumps.[62277]

PHARMACOKINETICS

Meropenem; vaborbactam is administered intravenously. The plasma protein binding is approximately 2% for meropenem and 33% for vaborbactam. The steady-state volume of distribution is 20.2 L for meropenem and 18.6 L for vaborbactam.
 
A minor pathway of meropenem elimination is hydrolysis of the beta-lactam ring (meropenem open lactam). Vaborbactam does not undergo metabolism. Both meropenem and vaborbactam are primarily excreted via the kidneys. Approximately 40% to 60% of a meropenem dose is excreted in the urine unchanged within 24 to 48 hours with a further 22% recovered as the microbiologically inactive hydrolysis product. Fecal elimination of meropenem accounts for approximately 2% of the dose. For vaborbactam, 75% to 95% of the dose is excreted unchanged in the urine over a 24 to 48 hour period. The half-lives are 1.22 hours for meropenem and 1.68 hours for vaborbactam.
 
Affected cytochrome P450 isoenzymes and/or drug transporters: OAT1, OAT3
Meropenem is a substrate of OAT1 and OAT3 transporters in the proximal tubule of the kidney. Carbapenems have not shown the potential for CYP450 inhibition or induction. Vaborbactam does not inhibit or induce any CYP450 isoenzymes, nor does it inhibit any hepatic or renal transporters. Vaborbactam is also not a substrate of these isoenzymes or transporters.