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Meropenem–Vaborbactam (Vabomere™): Another Option for Carbapenem-Resistant Enterobacteriaceae
Carbapenem-resistant Enterobacteriaceae (CRE) has been declared as one of the most urgent drug-resistant threats to the United States.1 Resistance can occur through several different mechanisms, one of which includes the production of broad-spectrum beta-lactamases. These enzymes can hydrolyze and inactivate all beta-lactam antibiotics, including carbapenems, leading to limited treatment options. Klebsiella pneumoniae carbapenamase (KPC) is among the most common carbapenemases produced by gram-negative bacteria.2–4 Mortality rates associated with CRE infections have been reported to be 40% and higher.3,5
Traditional antibiotics with activity against CRE include polymyxins, aminoglycosides, and tigecycline. These antibiotics, however, are associated with significant toxicity, unfavorable pharmacokinetic (PK) profiles, and poor outcomes when used as monotherapy in the treatment of CRE infections.3,6–8 A more recent antibiotic, ceftazidime–avibactam (FDA-approved in 2015), has shown improved efficacy and safety outcomes compared to traditional agents, but reports of treatment failure and resistance during the course of therapy have been documented.9–11 Meropenem–vaborbactam was approved by the FDA in August 2017 as the first carbapenem beta-lactamase inhibitor combination with activity against broad-spectrum beta-lactamases in CRE infections.
Meropenem–vaborbactam is indicated for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, in adults aged 18 years and older.
Meropenem, a carbapenem antibacterial agent, disrupts bacterial cell-wall synthesis by inhibiting penicillin-binding proteins causing cell death. Vaborbactam is a non-suicidal, boronic acid beta-lactamase inhibitor with no antibacterial activity. It prevents beta-lactamases, such as KPCs, from hydrolyzing meropenem.
SPECTRUM OF ANTIMICROBIAL ACTIVITY12
Meropenem–vaborbactam has demonstrated in vitro activity and in vivo clinical efficacy against most isolates of Enterobacter cloacae species complex, Escherichia coli, and Klebsiella pneumoniae. In vitro data are available with unknown clinical significance for these gramnegative bacteria: Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Klebsiella oxytoca, Morganella morgannii, Proteus mirabilis, Providencia spp., Pseudomonas aeruginosa, and Serratia marcescens. Minimum inhibitory concentration (MIC) data for meropenem–vaborbactam are provided in
The PK properties of vaborbactam have been evaluated alone and in combination with meropenem. A phase 1 study conducted among 80 healthy volunteers who were randomized to receive either single or ascending doses of vaborbactam showed that total drug exposure increased in proportion to dosing. Peak plasma concentrations (Cmax) following a three-hour infusion of 250 mg to 2,000 mg were measured as follows: 5.03 +/− 0.86 μg/mL to 41.6 +/− 4.75 μg/mL with single doses versus 4.81 +/− 1.04 μg/mL to 40.9 +/− 4.68 μg/mL with multiple doses administered over seven days. The average area under the curve (AUC0-τ) of vaborbactam administered as multiple doses was 16.03 +/− 3.56 μg•h/mL to 145 +/− 15.8 μg•h/mL, with no accumulation of either drug after infusion.14 When evaluated in combination with meropenem 1 g and 2 g, similar dose-proportional increases in plasma PK exposure were reported, with maximum concentrations achieved at the end of the three-hour infusion. No significant PK interactions were identified with concomitant administration.15
Meropenem is widely and readily distributed through various tissues and bodily fluids with a steady state volume of distribution of 20.2 L.12 In healthy volunteers, the average steady state volume of distribution following a single dose of vaborbactam 2 g IV was 21.8 +/− 2.26 L.14 The values were similar to those observed when administered as a single combination dose of 2 g/2 g (21.7 L for meropenem and 22 L for vaborbactam).15 The half-life of meropenem was 1.3 hours and for vaborbactam, 1.9 hours.15
Both agents are renally eliminated with approximately 40% to 60% of meropenem excreted unchanged in the urine. Twenty-two percent of meropenem is converted to inactive metabolites through hydrolysis of the beta-lactam ring. No metabolic pathway has been reported for vaborbactam. When administered at doses of 2 g intravenously (IV), approximately 75% to 95% of vaborbactam is found in the urine within 24 to 48 hours.12
Similar to other beta-lactams, meropenem displays time-dependent bactericidal killing. The pharmacodynamic (PD) index that best correlates with the efficacy of meropenem is the percentage of time of a dosing interval that the unbound plasma concentration of meropenem exceeds the meropenem–vaborbactam MIC against the infecting organism. The ratio of the 24-hour unbound plasma concentration of vaborbactam AUC to meropenem–vaborbactam MIC is the PD index that best depicts the efficacy of vaborbactam in combination with meropenem.
To evaluate the efficacy and safety of meropenem–vaborbactam, two phase 3, randomized, multicenter, clinical trials were conducted.
The TANGO I trial included adult patients with cUTI or acute pyelonephritis randomized to receive either meropenem–vaborbactam 2 g/2 g IV every eight hours administered as a three-hour infusion, or piperacillin–tazobactam 4 g/0.5 g IV every eight hours administered over 30 minutes for a minimum of five days, with the option to transition to oral levofloxacin 500 mg daily, when clinically indicated, for a total antibiotic duration of 10 days. Treatment duration was extended up to 14 days in patients with concurrent bacteremia. Notably, patients with perinephric and renal abscesses, acute or chronic bacterial prostatitis, orchitis, epididymitis, severe sepsis syndrome, immune deficiency, hemodialysis, or estimated creatinine clearance (based on Cockcroft-Gault) less than 30 mL/min were among those excluded from the study. Efficacy was assessed based on criteria by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) among the microbiologic modified intent-to-treat (ITT) and microbiologic evaluable patient groups. Primary FDA endpoints included overall success defined as clinical cure and microbial eradication at end of IV treatment, while the EMA’s efficacy endpoint was microbial eradication at test-of-cure (TOC) visit among both groups.
A total of 550 patients were randomized; of these, 545 patients received at least one dose of the study drug. Three hundred seventy-four patients had at least one bacterial pathogen isolated in baseline urine culture (105 colony-forming units/mL) and they represented the microbiologic modified ITT group. Both groups were well matched, with similar baseline characteristics. Escherichia coli (65.1% and 64.3%, respectively) and Klebsiella pneumoniae (15.6% and 15.4%, respectively) were the two most common bacterial pathogens recovered, with an estimated 12% of organisms reported as resistant to piperacillin–tazobactam. Resistance to meropenem was reported in only three patients with Klebsiella pneumoniae (3.3% of the microbiologic modified ITT group vs. 7.4% of the microbiologic evaluable group) and in none with Escherichia coli. For the primary efficacy endpoint, meropenem–vaborbactam was found to be non-inferior to piperacillin–tazobactam, with an overall success rate of 98.4% versus 94%, difference 4.5% [95% CI, 0.7%–9.1%]. This also met pre-specified statistical criteria for superiority over piperacillin–tazobactam. Non-inferiority was achieved based on the EMA-defined primary endpoint of microbial eradication, which was demonstrated in both the microbiologic modified ITT group (66.7% vs. 57.7%, difference 9% [95% CI, −0.9%–18.7%]), as well as in the microbiologic evaluable group (66.3% vs. 60.4%, difference 5.9% [95% CI, −4.2%–16%]). Overall success rates at TOC were higher among the treatment group-than in the microbiologic evaluable group (74.5% vs. 70.3%, difference 4.1% [95% CI, −4.9–9.1]), with clinical cure rates of 90.6% versus 86.3% of patients, difference 4.4 [95% CI, −2.2–11.1]. In assessing the safety of the antibiotic, treatment-related adverse outcomes were reported in 15.1% of microbiologic modified ITT group versus 12.8% of microbiologic evaluable patients, the most common being mild or moderate headache (8.8% vs. 4.4%, respectively) and diarrhea (3.3% vs. 4.4%, respectively). Adverse events resulting in discontinuation of therapy was 2.6% versus 5.1%, with low rates of overall study discontinuation (1.1%).
The TANGO-II trial, a randomized, multicenter, open-label study, was designed to compare the efficacy, safety, and tolerability of meropenem–vaborbactam with best available therapy (BAT) in patients with CRE infections. Carbapenem resistance was defined based on Clinical Laboratory and Standards Institute criteria, and BAT included combination or monotherapy treatment with any of the following antibiotics: carbapenem (meropenem, imipenem, ertapenem), tigecycline, colistin, polymyxin B, aminoglycoside (IV amikacin, gentamicin, tobramycin), and ceftazidime/avibactam (as monotherapy only). Adult patients with suspected or confirmed CRE infections were randomized in a 2:1 ratio to receive either meropenem–vaborbactam 2 g/2 g IV every eight hours or BAT for seven to 14 days. Infection types included bacteremia, cUTI or acute pyelonephritis, hospital-acquired or ventilator-acquired pneumonia, or complicated intra-abdominal infection (cIAI). Patients with immune deficiency and renal impairment on hemodialysis were also included in the study analysis. Clinical cure at end of therapy (EOT) and TOC, along with 28-day all-cause mortality, were evaluated as key efficacy endpoints. Microbiologic, safety, and tolerability outcomes were also compared between the treatment groups.
A total of 72 patients were enrolled in TANGO-II, of whom 43 had confirmed CRE infections. Twenty-eight patients received the study drug versus 15 patients who received BAT. Dual combination therapy was most commonly administered in the BAT group (46.7%), followed by monotherapy (26.7%) with either an aminoglycoside (6.7%), carbapenem (6.7%), ceftazidime–avibactam (6.7%), or polymyxin B/colistin therapy (6.7%). Baseline characteristics were comparable among both study groups and included patients with systemic inflammatory syndrome (41.9%), significant comorbidities based on a Charlson comorbidity index score of ≥ 5 (76.7%), and immune deficiency (41.9%). Bacteremia was identified as the most common infection type (46.5%), followed by cUTI and acute pyelonephritis (34.9%). Klebsiella pneumoniae was reported in 86% of all patients with an isolated baseline gram-negative pathogen.
Overall, clinical cure rates were found to be higher in the meropenem–vaborbactam group than the BAT group, both at EOT (64.3% vs. 33.3%, P = 0.04) and TOC (57.1% vs. 26.7%, P = 0.04). A reduction in 28-day mortality was also reported with meropenem–vaborbactam versus BAT (17.9% vs. 33.3%), which was observed across different infection types. Nine patients with prior antibiotic failure received meropenem–vaborbactam. When adjusted to exclude these patients, mortality rates were significantly lower among the meropenem–vaborbactam group compared to the BAT group (5.3% vs. 33.3%, P = 0.03).
Safety assessment included the evaluation of both treatment and renal-related adverse outcomes. Treatment-emergent adverse events (TEAEs) occurred in 87.1% of all patients, with a lower incidence of drug-related events reported among meropenem–vaborbactam patients compared to BAT patients (24.4% vs. 44%). No drug-related serious adverse events were observed among patients receiving meropenem–vaborbactam versus BAT (0% vs. 8%). Renal-related, treatment-related adverse events were also evaluated, of which the meropenem–vaborbactam group demonstrated lower incidences compared to the BAT group. These included acute renal failure and impairment, nephrotoxicity (based on an increase in post-baseline creatinine of ≥ 0.5 mg/dL [11.9% vs. 27.3%]), and a significantly improved risk–benefit profile when assessing clinical failure or nephrotoxicity (32.1% vs. 80%, P < 0.001), 28-day all-cause mortality or renal adverse events (21.4% vs. 60%, P < 0.01), and clinical failure or renal adverse events (32.1% vs. 80%, P < 0.001). Efficacy outcomes evaluated among patients with immune deficiency (n = 18) also favored meropenem–vaborbactam over BAT, with improved clinical cure rates at both EOT and TOC.
As reported in TANGO-I, meropenem–vaborbactam was discontinued in 2.9% (8/272) of patients due to hypersensitivity (1.1%, 3/272) and infusion-related reactions (0.7%, 2/272). Death occurred in two (0.7%) patients receiving meropenem–vaborbactam. Common adverse reactions in 3% or more of patients include headache, infusion site reactions (phlebitis, thrombosis, and erythema), and diarrhea. Adverse reactions in more than 1% of patients include hypersensitivity (drug hypersensitivity, anaphylactic reaction, rash urticarial, and bronchospasm), nausea, elevated alanine aminotransferase, elevated aspartate aminotransferase, pyrexia, and hypokalemia.
Co-administration of carbapenems, including meropenem, and valproic acid or divalproex sodium results in decreased serum concentrations of valproic acid. A reduction in valproic acid concentrations below the therapeutic range may increase breakthrough seizure risk. Supplemental anti-convulsant therapy should be considered if administration of meropenem–vaborbactam with valproic acid is necessary. Probenecid can increase plasma concentrations of meropenem by competing with meropenem for active tubular secretion. Co-adminstration of probenicid and meropenem–vaborbactam is not recommended.
Insufficient data exists to establish meropenem–vaborbactam’s safety in pregnant and breastfeeding women. Fetal malformations were observed in rabbits receiving various doses of IV vaborbactam, but it is not known if drug-associated birth defects occur in humans. Meropenem is excreted in breast milk, but little is known about the excretion of vaborbactam. Also, the drug has not been studied in pediatric patients aged 18 years and younger. Dosage adjustments are necessary in patients with renal impairment (see Dosage, Administration, Storage, and Stability section).
WARNING AND PRECAUTIONS12
Serious and fatal hypersensitivity reactions and serious skin reactions have been reported in patients receiving beta-lactam antibiotics. It is imperative to obtain a full history of documented beta-lactam allergies and to inquire about previous hypersensitivity reactions to beta-lactams. Meropenem–vaborbactam should be discontinued immediately if an allergic reaction occurs.
Meropenem has been associated with seizures and other adverse central nervous system experiences, such as focal tremors and myoclonus. Close adherence to the recommended dose is strongly advised, especially in patients with known factors that predispose them to convulsive activity (e.g., history of seizures, brain lesions, or bacterial meningitis). Additionally, co-administration of meropenem and valproic acid should be avoided as meropenem can decrease valproic acid serum concentrations and increase the risk of breakthrough seizures.
Clostridium difficile-associated diarrhea (CDAD) has been associated with almost all antibiotics, including meropenem–vaborbactam, and must be considered in all patients who present with diarrhea following antibiotic use. If CDAD is suspected or confirmed, meropenem–vaborbactam may need to be discontinued and appropriate CDAD-management initiated.
Meropenem–vaborbactam is administered at 4 g IV every 8 hours for up to 14 days in patients with an estimated glomerular filtration rate (eGFR) greater than 50 mL/min/1.73m2. Four grams of meropenem–vaborbactam consists of 2 g of meropenem and 2 g of vaborbactam, and should be administered as a prolonged infusion over three hours. Because of the renal excretion of the drug, dosage adjustments are recommended for an eGFR < 50 mL/min/1.73m2, as indicated in
Meropenem–vaborbactam is supplied in single-dose vials in dry-powder form. Each vial contains 1g of meropenem and 1g of vaborbactam (2 g of meropenem–vaborbactam) that must be constituted and further diluted prior to IV administration. The diluted solution must be infused and completed within four hours of preparation if stored at room temperature, or within 22 hours if kept refrigerated at 2°C to 8°C (36°F–46°F). Dry-powder vials should be stored at a controlled room temperature between 20°C to 25°C (68°F–77°F).
The average wholesale price (AWP) for a vial of meropenem 1 g/vaborbactam 1 g is $198.19 The total cost for a course of meropenem–vaborbactam depends on the patient’s renal function. For example, a patient with a cUTI with an eGFR > 50mL/min/1.73m2 requires a dose of meropenem–vaborbactam 4 g every eight hours for 10 to 14 days.12 This amounts to six vials per day, resulting in a total drug cost of $11,880 to $16,632 per treatment.
P&T COMMITTEE CONSIDERATIONS
Meropenem–vaborbactam is the first in its class of a combined carbapenem and beta-lactamase inhibitor with activity against KPC-producing gramnegative bacteria. Its improved efficacy and toxicity profile, and predictable PK parameters, make meropenem–vaborbactam a favorable treatment option for CRE infections, particularly when compared with current antibiotic agents. Although meropenem–vaborbactam is FDA-approved only for cUTI and acute pyelonephritis, its mortality benefit and efficacy outcomes observed across different infection types (as demonstrated in TANGO-II) suggest a preferential role in the management of these highly complicated infections.
As resistance emergence is a concern with any anti-infective agent, meropenem–vaborbactam should be reserved for infections that are proven or strongly suspected to be caused by a carbapenem-resistant gram-negative pathogen. Antimicrobial stewardship programs should promote judicious use of the antibiotic with establishment of criteria-for-use and susceptibility testing, as well as restriction by an Infectious Diseases specialist.
With the increasing prevalence of CRE infections and poor outcomes of traditional antibiotic therapies, meropenem–vaborbactam is an important addition to CRE treatments. However, its use should be carefully managed by antimicrobial stewardship programs to preserve its effectiveness and prevent the emergence of resistance.
Susceptibility Interpretive Criteria for Meropenem–Vaborbactam
|Pathogen||Minimum Inhibitory Concentration (mcg/mL)|
|Enterobacteriaceae||≤ 4/8||8/8||≥ 16/8|
Renal Dosing of Meropenem–Vaborbactam
|eGFR (mL/min/1.73m2)||Dose||Dosing Interval|
|−50||4 grams||Every 8 hours|
|30–49||2 grams||Every 8 hours|
|15–20||2 grams||Every 12 hours|
|< 15||1 gram||Every 12 hours|
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- CDC. Facility guidance for control of carbapenem-resistant Enterobacteriaceae (CRE)—November 2015 update CRE toolkit Available at: https://www.cdc.gov/hai/pdfs/cre/CRE-guidance-508.pdf. Accessed January 24, 2019
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- Daikos GL, Tsaousi S, Tzouvelekis LS, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems [published online February 10, 2014]. Antimicrob Agents Chemother 2014;58;(4):2322–2328.
- Alexander EL, Loutit J, Tumbarello M, et al. Carbapenem-resistant Enterobacteriaceae infections: results from a retrospective series and implications for the design of prospective clinical trials. Open Forum Infect Dis 2017;4;(2): ofx063
- Jorgensen SCJ, Rybak MJ. Meropenem and vaborbactam: stepping up the battle against carbapenem-resistant Enterobacteriaceae [published online March 28, 2018]. Pharmacotherapy 2018;38;(4):444–461.
- Shields RK, Nguyen MH, Chen L, et al. Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother 2017;61;(8):e00883–17.
- van Duin D, Lok JJ, Earley M, et al. Colistin vs. ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Clin Infect Dis 2018;66;(2):163–171.
- Shields RK, Potoski BA, Haidar G, et al. Clinical outcomes, drug toxicity, and emergence of ceftazidime-avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections [published online September 13, 2016]. Clin Infect Dis 2016;63;(12):1615–1618.
- Vabomere® (meropenem/vaborbactam) prescribing information Parsippany, New Jersey: Melinta Therapeutics, Inc.. 2017; Available at: http://www.vabomere.com/media/pdf/vabomere-us-prescribing-information.pdf.
- IBM Micromedex® DRUGDEX®. Meropenem–vaborbactam IBM Watson Health. Greenwood Village, Colorado: Available at: https://www.micromedexsolutions.com. Accessed January 24, 2019
- Griffith DC, Loutit JS, Morgan EE, et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of the beta-lactamase inhibitor vaborbactam (RPX7009) in healthy adult subjects. Antimicrob Agents Chemother 2016;60;(10):6326–6332.
- Rubino CM, Bhavnani SM, Loutit JS, et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of vaborbactam and meropenem alone and in combination following single and multiple doses in healthy adult subjects. Antimicrob Agents Chemother 2018;62;(4):e02228–17.
- Keith SK, Bhowmick T, Metallidis S, et al. Effect of meropenem–vaborbactam vs. Pipperacillin–Tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trial. JAMA 2018;319;(8):788–799.
10.1001/jama.2018.0438 Kaye KS, Vazquez J, Mathers A, et al. Meropenem–vaborbactam (Vabomere) vs. best available therapy for CRE infections: TANGO II randomized, controlled phase 3 study results. Presentation at ID Week 2017 San Diego, California October 4–8, 2017 Wunderink R, Giamarellos-Bourboulis EJ, Rahav G, et al. Meropenem–vaborbactam (Vabomere) vs. best available therapy for carbapenem-resistant Enterobacteriaceae infections in TANGO II: primary outcomes by site of infection. Presentation at ID Week 2017 San Diego, California October 4–8, 2017
- Red Book Online Ann Arbor, Michigan: Truven Health Analytics. Accessed January 31, 2019