Mechanism of Action
The meropenem component of VABOMERE 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 beta‑lactamases, including penicillinases and cephalosporinases produced by gram‑negative and gram‑positive bacteria, with the exception of carbapenem hydrolyzing beta‑lactamases.
The vaborbactam component of VABOMERE 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. Vaborbactam does not decrease the activity of meropenem against meropenem-susceptible organisms.
Mechanisms of beta-lactam resistance may include the production of beta-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 beta-lactamases, express varying levels of beta-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 beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: KPC, SME, TEM, SHV, CTX‑M, CMY, and ACT.
VABOMERE is not active against bacteria that produce metallo‑beta 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 beta‑lactamases, were susceptible to VABOMERE (minimum inhibitory concentration ≤4 mcg /mL). These isolates produced one or more beta‑lactamases of the following enzyme groups: OXA (non‑carbapenemases), KPC, CTX-M, TEM, SHV, CMY, and ACT.
Some beta-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 beta-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 (e.g., mouse thigh infection, urinary tract infection and pulmonary infection) caused by some meropenem non-susceptible KPC-producing Enterobacteriaceae.
VABOMERE has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage ( 1.1)] .
- Enterobacter cloacae species complex
- Escherichia coli
- Klebsiella pneumoniae
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.
- Citrobacter freundii
- Citrobacter koseri
- Enterobacter aerogenes
- Klebsiella oxytoca
- Morganella morganii
- Proteus mirabilis
- Providencia spp.
- Pseudomonas aeruginosa
- Serratia marcescens
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid in selecting the most appropriate antibacterial drug for treatment.
Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method 2,3 (broth and/or agar). The MIC values should be determined using serial dilutions of meropenem combined with a fixed concentration of 8 mcg/mL of vaborbactam. The MIC values should be interpreted according to the criteria in Table 6.
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method 3,4. This procedure uses paper disks impregnated with 20 mcg of meropenem and 10 mcg vaborbactam to test the susceptibility of bacteria to meropenem and vaborbactam. The disk breakpoints are provided in Table 6.
Minimum Inhibitory Concentrations
(zone diameters in mm)
S = Susceptible; I = Intermediate; R = Resistant
A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy of supplies and reagents used in the assay, and the techniques of the individuals performing the test 2,3,4. Standard meropenem and vaborbactam powder should provide the following range of MIC values noted in Table 7. For the diffusion technique using the 20 mcg meropenem/10 mcg vaborbactam disk, the criteria in Table 6 should be achieved
|Quality Control Strain|| |
Minimum Inhibitory Concentration
(zone diameter in mm)
|Klebsiella pneumoniae ATCC BAA-1705*||0.015/8-0.06/8||
|Klebsiella pneumoniae ATCC BAA-2814*||-||16-20|
|Pseudomonas aeruginosa ATCC 27853||0.12/8-1/8||29-35|
|Escherichia coli ATCC 25922||0.008/8-0.06/8||31-37|
|Escherichia coli ATCC 35218||0.008/8-0.06/8||-|
|Klebsiella pneumoniae ATCC 700603||0.015/8-0.06/8||29-35|
|Staphylococcus aureus ATCC 25923||-||32-38|
|Staphylococcus aureus ATCC 29213||
ATCC = American Type Culture Collection
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