Carbapenem and Beta-Lactamase Inhibitor Combination Antibiotics
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Constitute the appropriate number of vials as needed for the dose.
2 vials are used for 4 g (2 g meropenem and 2 g vaborbactam) dose.
1 vial is used for 2 g (1 g meropenem and 1 g vaborbactam) or 1 g (0.5 g meropenem and 0.5 g vaborbactam) doses.
Withdraw 20 mL of 0.9% Sodium Chloride Injection from an infusion bag and constitute each vial.
For 4 g (2 g meropenem and 2 g vaborbactam) dose, use an infusion bag with a volume of 250, 500, or 1,000 mL.
For 2 g (1 g meropenem and 1 g vaborbactam) dose, use an infusion bag with a volume of 125, 250, or 500 mL.
For 1 g (0.5 g meropenem and 0.5 g vaborbactam) dose, use an infusion bag with a volume of 70, 125, or 250 mL.
Mix gently to dissolve. The constituted solution will have approximate concentrations of 0.05 g/mL meropenem and 0.05 g/mL vaborbactam. The final volume is approximately 21.3 mL.
The constituted solution must be further diluted before use; it is not for direct injection.
Storage: Constituted solution must be further diluted immediately.
Withdraw the full or partial constituted vial contents from each vial and add back into the 0.9% Sodium Chloride Injection infusion bag.
For a 4 g (2 g meropenem and 2 g vaborbactam) dose, using an infusion bag with a volume of 250, 500, or 1,000 mL, the final infusion concentration of meropenem; vaborbactam will be 16 mg/mL, 8 mg/mL, and 4 mg/mL, respectively.
For a 2 g (1 g meropenem and 1 g vaborbactam) dose, using an infusion bag with a volume of 125, 250, or 500 mL, the final infusion concentration of meropenem; vaborbactam will be 16 mg/mL, 8 mg/mL, and 4 mg/mL, respectively.
For a 1 g (0.5 g meropenem and 0.5 g vaborbactam) dose, using an infusion bag with a volume of 70, 125, or 250 mL, the final infusion concentration of meropenem; vaborbactam will be 14.3 mg/mL, 8 mg/mL, and 4 mg/mL, respectively.
Storage: The infusion of the diluted solution must be completed within 4 hours if stored at room temperature or 22 hours if refrigerated at 2 to 8 degrees C (36 to 46 degrees F).
Intermittent IV Infusion:
Administer over 3 hours.
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
Common Brand Names
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
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 Impairment
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.
Meropenem and vaborbactam are removed by hemodialysis. For patients maintained on hemodialysis, administer meropenem; vaborbactam after the hemodialysis session.
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.
VABOMERE Intravenous Inj Pwd: 1-1g
12 g/day (6 g meropenem and 6 g vaborbactam) IV.Geriatric
12 g/day (6 g meropenem and 6 g vaborbactam) IV.Adolescents
Safety and efficacy have not been established.Children
Safety and efficacy have not been established.Infants
Safety and efficacy have not been established.Neonates
Safety and efficacy have not been established.
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.  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.  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). 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. 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.
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.
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.      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. 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. 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.   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.
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. 
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. 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.    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. 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.  Meropenem; vaborbactam may not have activity against gram-negative bacteria that have porin mutations combined with overexpression of efflux pumps.
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.
After multiple doses of meropenem; vaborbactam 4 g (2 g meropenem and 2 g vaborbactam) in healthy adults, the Cmax are 43.4 mg/L for meropenem and 55.6 mg/L for vaborbactam. The AUCs are 138 mg x hour/L for meropenem and 196 mg x hour/L for vaborbactam. The Cmax and AUC increase proportionally with increased doses. There is no accumulation of either meropenem or vaborbactam after multiple IV doses administered every 8 hours for 7 days in patients with normal renal function.
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.