Mechanism Of Action
VABOMERE is an antibacterial
drug [see Microbiology].
Similar to other beta-lactam antibacterial drugs, the
percentage of time of a dosing interval that unbound plasma concentration of
meropenem exceeds the meropenem-vaborbactam minimum inhibitory concentration
(MIC) against the infecting organism has been shown to best correlate with
efficacy in animal and in vitro models of infection. 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 of infection.
Pharmacokinetic (PK) Parameters
The mean PK parameters of meropenem and vaborbactam in
healthy adults with normal renal function after single and multiple 3-hour
infusions of VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams)
administered every 8 hours are summarized in Table 4.
The PK parameters of meropenem and vaborbactam were
similar for single and multiple dose administration of VABOMERE.
Table 4: Pharmacokinetic Parameters (Mean [SD]) of
Meropenem and Vaborbactam Following Administration of VABOMERE 4 grams
(meropenem 2 grams and vaborbactam 2 grams) by 3-hour Infusion in Healthy Adult
|Single VABOMERE 4 grama Dose
|Multiple VABOMERE 4 grama Doses Administered Every 8 hours for 7 Days
|Single VABOMERE 4 grama Dose
|Multiple VABOMERE 4 grama Doses Administered Every 8 hours for 7 Days
|Cmax = maximum observed concentration; CL = plasma
clearance; AUC = area under the concentration time curve; T½ = half-life.
a Meropenem 2 grams and vaborbactam 2 grams administered as a 3-hour
b AUC0-inf reported for single-dose administration; AUC0-8 reported
for multiple-dose administration; AUC0 – 24 is 414 mg•h/L for meropenem and 588
mg•h/L for vaborbactam.
The maximum plasma concentration (Cmax) and area under the plasma drug concentration time curve
(AUC) of meropenem and vaborbactam proportionally increased with dose across
the dose range studied (1 gram to 2 grams for meropenem and 0.25 grams to 2
grams for vaborbactam) when administered as a single 3-hour intravenous infusion.
There is no accumulation of meropenem or vaborbactam following multiple
intravenous infusions administered every 8 hours for 7 days in subjects with
normal renal function.
The mean population PK parameters of meropenem and vaborbactam
in 295 patients (including 35 patients with reduced renal function) after
3-hour infusions of VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2
grams) administered every 8 hours (or dose adjusted based on renal function)
are summarized in Table 5.
Table 5: Population Pharmacokinetic Parameters (Mean
[SD]) of Meropenem and Vaborbactam Following Administration of VABOMERE 4 grams
(meropenem 2 grams and vaborbactam 2 grams) by 3-hour Infusion in Patientsa
|AUC0-24, Day 1 (mg•h/L)
|AUC0-24, steady-state (mg•h/L)
|a Meropenem 2 grams and vaborbactam 2 grams
administered as a 3-hour infusion.
The plasma protein binding of meropenem is approximately
2%. The plasma protein binding of vaborbactam is approximately 33%.
The steady-state volumes of distribution of meropenem and
vaborbactam in patients were 20.2 L and 18.6 L, respectively.
clearance of meropenem in healthy subjects following multiple doses is 15.1 L/h
and for vaborbactam is 10.9 L/h. The t½ is 1.22 hours and 1.68 hours for meropenem
and vaborbactam, respectively.
A minor pathway of meropenem elimination is hydrolysis of
the beta-lactam ring (meropenem open lactam), which accounts for 22% of a dose
eliminated via the urine.
Vaborbactam does not undergo metabolism.
Both meropenem and vaborbactam are primarily excreted via
Approximately 40–60% of a meropenem dose is excreted
unchanged within 24-48 hours with a further 22% recovered as the
microbiologically inactive hydrolysis product. The mean renal clearance for
meropenem was 7.8 L/h. The mean non-renal clearance for meropenem was7.3 L/h
which comprises both fecal elimination (~2% of dose) and degradation due to
For vaborbactam, 75 to 95% of the dose was excreted
unchanged in the urine over a 24 to 48 hour period. The mean renal clearance
for vaborbactam was 8.9 L/h. The mean non-renal clearance for vaborbactam was
2.0 L/h indicating nearly complete elimination of vaborbactam by the renal
Patients With Renal Impairment
Following a single dose of VABOMERE, pharmacokinetic
studies with meropenem and vaborbactam in subjects with renal impairment have
shown that meropenem AUC0-inf ratios to subjects with normal renal function are
1.28, 2.07, and 4.63 for subjects with mild (eGFR of 60 to 89 mL/min/1.73m²),
moderate (eGFR of 30 to 59 mL/min/1.73m²), and severe (eGFR <30
mL/min/1.73m²) renal impairment, respectively; vaborbactam AUC0-inf 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 [see DOSING AND
ADMINISTRATION]. Hemodialysis removed 38% of the meropenem dose and 53% of
the vaborbactam dose. Vaborbactam exposure was high in subjects with ESRD (eGFR
<15 ml/min/1.73 m²). Vaborbactam exposure was higher when VABOMERE was
administered after hemodialysis (AUC0-inf ratio to subjects with normal renal
function of 37.5) than when VABOMERE was administered before hemodialysis
(AUC0-inf ratio to subjects with normal renal function of 10.2) [see Use In Specific
Populations and DOSING AND ADMINISTRATION].
Patients With Hepatic Impairment
A pharmacokinetic study conducted with an intravenous
formulation of meropenem in patients with hepatic impairment has shown no
effects of liver disease on the pharmacokinetics of meropenem.
Vaborbactam does not undergo hepatic metabolism.
Therefore, the systemic clearance of meropenem and vaborbactam is not expected
to be affected by hepatic impairment.
In elderly patients with renal impairment, plasma
clearances of meropenem and vaborbactam were reduced, correlating with
age-associated reduction in renal function [see DOSAGE AND ADMINISTRATION
and Use In Specific Populations].
Male And Female Patients
Meropenem and vaborbactam Cmax and AUC were similar
between males and females using a population pharmacokinetic analysis.
Racial Or Ethnic Groups
No significant difference in mean meropenem or
vaborbactam clearance was observed across race groups using a population
No drug-drug interaction was observed between meropenem
and vaborbactam in clinical studies with healthy subjects.
Based upon the in vitro and in vivo data available to
date, there is a low potential for clinically significant drug interactions
Vaborbactam at clinically relevant concentrations does
not inhibit the cytochrome P450 isoforms CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19,
CYP2D6, and CYP3A4 in vitro human liver microsomes. Vaborbactam showed no
potential for in vitro induction of CYP1A2, CYP2B6, and CYP3A4 in human
hepatocytes. Studies evaluating the potential for meropenem to interact with
CYP450 enzymes or active transport systems have not been conducted. However,
carbapenems as a class have not shown the potential for inhibition or induction
CYP450 enzymes and clinical experience suggests that such effects are unlikely.
Vaborbactam does not inhibit the following hepatic and
renal transporters in vitro at clinically relevant concentrations: P-gp, BCRP,
OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3 or BSEP. Vaborbactam was not a
substrate of OAT1, OAT3, OCT2, P-gp, and BCRP.
Meropenem is a substrate of OAT1 and OAT3 and as such,
probenecid competes with meropenem for active tubular secretion and thus
inhibits the renal excretion of meropenem. Following administration of
probenecid with meropenem, the mean systemic exposure increased 56% and the mean
elimination half-life increased 38% [see DRUG INTERACTIONS].
Concomitant administration of meropenem and valproic acid
has been associated with reductions in valproic acid concentrations with
subsequent loss in seizure control [see DRUG INTERACTIONS].
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
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 betalactamases, 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
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
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
VABOMERE has been shown to be active against most
isolates of the following bacteria, both in vitro and in clinical infections
- Gram-negative bacteria
- 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
For specific information regarding susceptibility test
interpretive criteria and associated test methods and quality control standards
recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
Complicated Urinary Tract Infections (cUTI), Including Pyelonephritis
A total of 545 adults with cUTI, including pyelonephritis
were randomized into a double-blind, double dummy, multi-center trial comparing
VABOMERE (meropenem 2 grams and vaborbactam 2 grams) to piperacillin/tazobactam
(piperacillin 4 grams/tazobactam 0.5 grams) intravenously every 8 hours. Switch
to an oral antibacterial drug, such as levofloxacin was allowed after a minimum
of 15 doses of IV therapy.
The microbiologically modified intent to treat population
(m-MITT) included all randomized patients who received any study drug and had
at least 1 baseline uropathogen. Clinical and microbiological response at the
end of IV treatment (EOIVT) required both a clinical outcome of cure or
improvement and a microbiologic outcome of eradication (all baseline
uropathogens at >105 CFU/mL are to be reduced to <104 CFU/mL). Clinical
and microbiological response was also assessed at the Test of Cure (TOC) visit
(approximately 7 days after completion of treatment) in the m-MITT population
and required both a clinical outcome of cure and a microbiological outcome of
Patient demographic and baseline characteristics were
balanced between treatment groups in the m-MITT population. Approximately 93%
of patients were Caucasian and 66% were females in both treatment groups. The
mean age was 54 years with 32% and 42% patients greater than 65 years of age in
VABOMERE and piperacillin/tazobactam treatment groups, respectively. Mean body
mass index was approximately 26.5 kg/m² in both treatment groups. Concomitant
bacteremia was identified in 12 (6%) and 15 (8%) patients at baseline in
VABOMERE and piperacillin/tazobactam treatment groups respectively. The
proportion of patients with diabetes mellitus at baseline was 17% and 19% in
VABOMERE and piperacillin/tazobactam treatment groups, respectively. The
majority of patients (approximately 90%) were enrolled from Europe, and
approximately 2% of patients were enrolled from North America. Overall, in both
treatment groups, 59% of patients had pyelonephritis and 40% had cUTI, with 21%
and 19% of patients having a non-removable and removable source of infection,
Mean duration of IV treatment in both treatment groups
was 8 days and mean total treatment duration (IV and oral) was 10 days;
patients with baseline bacteremia could receive up to 14 days of therapy.
Approximately 10% of patients in each treatment group in the m-MITT population
had a levofloxacin-resistant pathogen at baseline and received levofloxacin as
the oral switch therapy. This protocol violation may have impacted the
assessment of the outcomes at the TOC visit. These patients were not excluded
from the analysis presented in Table 6, as the decision to switch to oral
levofloxacin was based on post-randomization factors.
VABOMERE demonstrated efficacy with regard to clinical
and microbiological response at the EOIVT visit and TOC visits in the m-MITT
population as shown in Table 6.
Table 6: Clinical and Microbiological Response Rates
in a Phase 3 Trial of cUTI Including Pyelonephritis (m-MITT Population)
||VABOMERE n/N (%)
||Piperacillin/ Tazobactam n/N (%)
||Difference (95% CI)
|Clinical cure or improvement AND microbiological eradication at the End of IV Treatment Visit*
|Clinical cure AND microbiological eradication at the Test of Cure visit approximately 7 days after completion of treatment**
|CI = confidence interval; EOIVT
= End of Intravenous Treatment; TOC = Test of Cure
*End of IV Treatment visit includes patients with organisms resistant to
piperacillin/tazobactam at baseline
**Test of Cure visit excludes patients with organisms resistant to
piperacillin/tazobactam at baseline
In the m-MITT population, the
rate of clinical and microbiological response in VABOMERE-treated patients with
concurrent bacteremia at baseline was 10/12 (83.3%).
In a subset of the E. coli and
K. pneumoniae isolates, genotypic testing identified certain ESBL groups (e.g.,
TEM, CTX-M, SHV and OXA) in both treatment groups of the Phase 3 cUTI trial.
The rates of clinical and microbiological response were similar in the ESBL-positive
and ESBL-negative subset at EOIVT; at TOC, clinical and microbiological
response was lower in the ESBL-positive as compared to ESBL-negative subset in
both treatment groups.