Microbiology1

The meropenem component of VABOMERE™ (meropenem and vaborbactam) is a penem antibacterial drug. The bactericidal action of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets. Meropenem is stable to hydrolysis by most β-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria, with the exception of carbapenem hydrolyzing β-lactamases.

The vaborbactam component of VABOMERE is a non-suicidal β-lactamase inhibitor that protects meropenem from degradation by certain serine β-lactamases such as Klebsiella pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity. Vaborbactam does not decrease the activity of meropenem against meropenem-susceptible organisms.

Mechanisms of β-lactam resistance may include the production of
β-lactamases, modification of PBPs by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin. VABOMERE may not have activity against gram-negative bacteria that have porin mutations combined with overexpression of efflux pumps.

Clinical isolates may produce multiple β-lactamases, express varying levels of
β-lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.

Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.

VABOMERE demonstrated in vitro activity against Enterobacteriaceae in the presence of some β-lactamases and extended-spectrum
β-lactamases (ESBLs) of the following groups: KPC, SME, TEM, SHV, CTX-M, CMY, and ACT. VABOMERE is not active against bacteria that produce metallo–β-lactamases or oxacillinases with carbapenemase activity.

In the Phase 3 cUTI trial with VABOMERE, some isolates of E. coli, K. pneumoniae, E. cloacae, C. freundii, P. mirabilis, P. stuartii that produced β-lactamases, were susceptible to VABOMERE (minimum inhibitory concentration ≤4 mcg/mL). These isolates produced one or more β-lactamases of the following enzyme groups: OXA (non-carbapenemases), KPC, CTX-M, TEM, SHV, CMY, and ACT.

Some β-lactamases were also produced by an isolate of K. pneumoniae that was not susceptible to VABOMERE (minimum inhibitory concentration ≥32 mcg/mL). This isolate produced β-lactamases of the following enzyme groups: CTX-M, TEM, SHV, and OXA.

No cross-resistance with other classes of antimicrobials has been identified. Some isolates resistant to carbapenems (including meropenem) and to cephalosporins may be susceptible to VABOMERE.

In vitro synergy studies have not demonstrated antagonism between VABOMERE and levofloxacin, tigecycline, polymyxin, amikacin, vancomycin, azithromycin, daptomycin, or linezolid.

Vaborbactam restored activity of meropenem in animal models of infection (eg, mouse thigh infection, urinary tract infection and pulmonary infection) caused by some meropenem nonsusceptible KPC-producing Enterobacteriaceae.

VABOMERE has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections.

Gram-negative bacteria:

  • Escherichia coli
  • Klebsiella pneumoniae
  • Enterobacter cloacae species complex

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro MIC less than or equal to the susceptible breakpoint for VABOMERE against isolates of a similar genus or organism group. However, the efficacy of VABOMERE in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-negative bacteria:

  • Citrobacter freundii
  • Citrobacter koseri
  • Enterobacter aerogenes
  • Klebsiella oxytoca
  • Morganella morganii
  • Proteus mirabilis
  • Providencia spp.
  • Pseudomonas aeruginosa
  • Serratia marcescens

The table below indicates which, if any, susceptibility test interpretive criteria information is available at: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm575163.htm.

Susceptibility Interpretive Criteria for Meropenem/Vaborbactam*

Pathogen Minimum Inhibitory
Concentrations
(mcg/mL)
Disk Diffusion
(zone diameters in mm)
S I R S I R
Enterobacteriaceae ≤4/8 8/8 ≥16/8 ≥17 14-16 ≤13

S = Susceptible; I = Intermediate; R = Resistant

*Information reviewed every 6 months to ensure accuracy.

Microbiology1

Mechanism of Action (MOA)

The meropenem component of VABOMERE™ (meropenem and vaborbactam) is a penem antibacterial drug. The bactericidal action of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets. Meropenem is stable to hydrolysis by most β-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria, with the exception of carbapenem hydrolyzing β-lactamases.

The vaborbactam component of VABOMERE is a non-suicidal β-lactamase inhibitor that protects meropenem from degradation by certain serine β-lactamases such as Klebsiella pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity. Vaborbactam does not decrease the activity of meropenem against meropenem-susceptible organisms.

Resistance

Mechanisms of β-lactam resistance may include the production of β-lactamases, modification of PBPs by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin. VABOMERE may not have activity against gram-negative bacteria that have porin mutations combined with overexpression of efflux pumps.

Clinical isolates may produce multiple β-lactamases, express varying levels of β-lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.

Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.

VABOMERE demonstrated in vitro activity against Enterobacteriaceae in the presence of some β-lactamases and extended-spectrum β-lactamases (ESBLs) of the following groups: KPC, SME, TEM, SHV, CTX-M, CMY, and ACT. VABOMERE is not active against bacteria that produce metallo–β-lactamases or oxacillinases with carbapenemase activity.

In the Phase 3 cUTI trial with VABOMERE, some isolates of E. coli, K. pneumoniae, E. cloacae, C. freundii, P. mirabilis, P. stuartii that produced β-lactamases, were susceptible to VABOMERE (minimum inhibitory concentration ≤4 mcg/mL). These isolates produced one or more β-lactamases of the following enzyme groups: OXA (non-carbapenemases), KPC, CTX-M, TEM, SHV, CMY, and ACT.

Some β-lactamases were also produced by an isolate of K. pneumoniae that was not susceptible to VABOMERE (minimum inhibitory concentration ≥32 mcg/mL). This isolate produced β-lactamases of the following enzyme groups: CTX-M, TEM, SHV, and OXA.

No cross-resistance with other classes of antimicrobials has been identified. Some isolates resistant to carbapenems (including meropenem) and to cephalosporins may be susceptible to VABOMERE.

Interaction With Other Antimicrobials

In vitro synergy studies have not demonstrated antagonism between VABOMERE and levofloxacin, tigecycline, polymyxin, amikacin, vancomycin, azithromycin, daptomycin, or linezolid.

Activity Against Meropenem Non-susceptible
Bacteria in Animal Infection Models

Vaborbactam restored activity of meropenem in animal models of infection (eg, mouse thigh infection, urinary tract infection and pulmonary infection) caused by some meropenem non-susceptible KPC-producing Enterobacteriaceae.

Antimicrobial Activity

VABOMERE has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections.

Gram-negative bacteria:

  • Escherichia coli
  • Klebsiella pneumoniae
  • Enterobacter cloacae species complex

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro MIC less than or equal to the susceptible breakpoint for VABOMERE against isolates of a similar genus or organism group. However, the efficacy of VABOMERE in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.


Gram-negative bacteria:

  • Citrobacter freundii
  • Citrobacter koseri
  • Enterobacter aerogenes
  • Klebsiella oxytoca
  • Morganella morganii
  • Proteus mirabilis
  • Providencia spp.
  • Pseudomonas aeruginosa
  • Serratia marcescens

Susceptibility Test Methods

The table below indicates which, if any, susceptibility test interpretive criteria information is available at: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm575163.htm.

Susceptibility Interpretive Criteria for Meropenem/Vaborbactam*

Pathogen Minimum Inhibitory
Concentrations
(mcg/mL)
Disk Diffusion
(zone diameters in mm)
S I R S I R
Enterobacteriaceae ≤4/8 8/8 ≥16/8 ≥17 14-16 ≤13

S = Susceptible; I = Intermediate; R = Resistant

*Information reviewed every 6 months to ensure accuracy.

ordering information

ordering information

See VABOMERE ordering information

DOSING VABOMERE

DOSING VABOMERE

Get details about VABOMERE dosing

Reference: 1. Vabomere [package insert]. Lincolnshire, IL: Melinta Therapeutics, Inc.; 2018.

INDICATIONS AND USAGE

VABOMERE™ (meropenem and vaborbactam) is indicated for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex.

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


IMPORTANT SAFETY INFORMATION

Contraindications

VABOMERE is contraindicated in patients with known hypersensitivity to any components of VABOMERE (meropenem and vaborbactam), or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactam antibacterial drugs.

Warnings and Precautions

  • Hypersensitivity reactions were reported in patients treated with VABOMERE in the clinical trials. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving therapy with beta-lactam antibacterial drugs. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another beta-lactam antibacterial drug. If an allergic reaction to VABOMERE occurs, discontinue the drug immediately.
  • Seizures and other adverse Central Nervous System (CNS) experiences have been reported during treatment with meropenem, which is a component of VABOMERE. Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity.
  • Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including VABOMERE, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued.
  • The concomitant use of VABOMERE and valproic acid or divalproex sodium is generally not recommended. Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. If administration of VABOMERE is necessary, consider supplemental anticonvulsant therapy.
  • In patients with renal impairment, thrombocytopenia has been observed in patients treated with meropenem, but no clinical bleeding has been reported.
  • Alert patients receiving VABOMERE on an outpatient basis regarding adverse reactions such as seizures, delirium, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment.
  • Prescribing VABOMERE in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of drug-resistant bacteria.
  • As with other antibacterial drugs, prolonged use of VABOMERE may result in overgrowth of nonsusceptible organisms.

Adverse Reactions

The most frequently reported adverse reactions occurring in ≥3% of patients treated with VABOMERE were headache, phlebitis/infusion site reactions, and diarrhea.

Please see Full Prescribing Information.