By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved a new combination antibacterial for the treatment of complicated urinary tract infections. The new antibacterial combines meropenem, a synthetic carbapenem available since 1996, and a new beta-lactamase inhibitor called vaborbactam. This is the second new beta-lactamase inhibitor to be approved after avibactam, which is combined with ceftazidime (Avycaz). Meropenem/vaborbactam was designated as a qualified infectious disease product and received a priority review. It is marketed as Vabomere.

INDICATIONS

Meropenem/vaborbactam is indicated for treating patients ≥ 18 years of age with complicated urinary tract infection (cUTI), including pyelonephritis caused by susceptible bacteria from the Enterobacteriaceae family of gram-negative bacteria.1 These include Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex.

DOSAGE

The recommended dose for adults is 4 grams (meropenem 2 grams and vaborbactam 2 grams) administered through an IV infusion (over three hours) every eight hours for up to 14 days.1 The dose should be reduced based on the degree of renal impairment (i.e., estimated glomerular filtration rate). Vabomere is available as 2 gram single-dose vials containing 1 gram each of meropenem and vaborbactam.

POTENTIAL ADVANTAGES

Vaborbactam, similar to avibactam, is a potent inhibitor of serine Ambler class A and class C beta-lactamases, with potent activity against Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria and other class A carbapenases.2 Older beta-lactamases such as clavulanic acid, sulbactam, and tazobactam, do not inhibit class A carbapenemases.

POTENTIAL DISADVANTAGES

Meropenem/vaborbactam is not active against bacteria that produce metallo-beta-lactamase or oxacillinases with carbapenemase activity.1 Meropenem/vaborbactam reduces the concentration of valproic acid and divalproex sodium. Concomitant use is not recommended.1 The most common adverse reactions were headache (8.8%) and phlebitis/infusion site reactions (4.4%).1

COMMENTS

The efficacy and safety of meropenem/vaborbactam were evaluated in a comparative, double-blind, double-dummy, clinical trial with 545 subjects with cUTI.1,3 The FDA defines cUTI as a clinical syndrome characterized by local and systemic signs and symptom, including fever, chills, malaise, flank pain, back pain, and/or costovertebral angle pain or tenderness that occur in the presence of functional or anatomical abnormality of the urinary tract or in the presence of catherization.4 Pyelonephritis is considered a subset of cUTI. Study participants primarily were Caucasian (93%), had a mean age of 54 years, and 59% had pyelonephritis. Subjects were randomized to meropenem/vaborbactam (2 grams each) or piperacillin (4 g/tazobactam 0.5g) every eight hours. Switching to an oral antibacterial was allowed after a minimum of 15 parenteral doses. Efficacy was evaluated by clinical and microbiological responses at the end of IV treatment and also at seven days after completion of treatment. The first assessment required clinical outcome of cure or improvement and an eradication of baseline uropathogens. The second required clinical cure and microbiological eradication. A total of 186 subjects in the meropenem/vaborbactam group and 175 in the piperacillin/tazobactam group met the condition for analysis (received study drug and demonstrated at least one baseline uropathogen). Success rates at the end of IV treatment were 98.4% for meropenem/vaborbactam and 94.3% for piperacillin/tazobactam. At approximately seven days after treatment completion, rates were 76.5% vs. 73.2%. The first outcome met criteria for non-inferiority and superiority, and the second outcome met criteria for non-inferiority.5

CLINICAL IMPLICATIONS

Gram-negative bacteria of the Enterobacteriaceae family are a common cause of urinary tract infections.2 They also are associated with antibiotic resistance by way of extended beta-lactamase production and carbapenem resistance. Vaborbactam is designed as a potent inhibitor of serine carbapenemases, particularly KPC.6 Meropenem/vaborbactam provides a new option, and should be reserved for cUTI caused by KPC-producing Enterobacteriaceae. The Data and Safety Monitoring Board ended a second clinical trial early because of efficacy benefit over best available therapy in serious infections due to carbapenem-resistant Enterobacteriaceae in adults.7,8 Best available therapy generally included aminoglycosides, polymyxin B, colistin, tigecycline, or various combination of these. Serious infections included cUTI, hospital-associated bacterial pneumonia, ventilator-associated bacterial pneumonia, and bacteremia. Meropenem/vaborbactam is expected to be available in the fourth quarter of 2017. Cost was not available at the time of this review.

REFERENCES

  1. Vabomere Prescribing Information. The Medicines Company. August 2017.
  2. Thaden JT, et al. Virulence 2017;8:403-416.
  3. ClinicalTrials.gov. Efficacy, Safety, Tolerability of Carbavance Compared to Piperacillin/Tazobactam in Complicated Urinary Tract Infections (cUTIs), Including Acute Pyelonephritis (AP), in Adults. Available at: http://bit.ly/2y0Srld. Accessed Oct. 4, 2017.
  4. U.S. Department of Health and Human Services. Complicated Urinary Tract Infections: Developing Drugs for Treatment. Guidance for Industry. Available at: http://bit.ly/2gbaqMe. Accessed Oct. 4, 2017.
  5. The Medicines Company. Carbavance Tango-1 Phase III Trial Results, June 27, 2017. Report PDF downloaded Oct. 4, 2017.
  6. Hecker SJ, et al. J Med Chem 2015;58: 3682-3692.
  7. ClinicalTrials.gov. Efficacy, Safety, Tolerability of Carbavance Compared to Best Available Therapy in Serious Infections Due to Carbapenem Resistant Enterobacteriaceae, in Adults. Available at: http://bit.ly/2kpc81c. Accessed Oct. 4, 2017.
  8. The Medicines Company. The Medicines Company announces TANGO-2 trial of meropenem-vaborbactam (formerly, Carbavance) stopped early for superior benefit-risk compared to best available therapy for CRE. Available at: http://bit.ly/2hjqpLk. Accessed Oct. 4, 2017.