New FDA Approval: Vabomere

New FDA Approval: Vabomere

Editor's note: The following is a guest post by Dev Chatterji, PharmD, BCPS. He's an infectious disease specialist, he's a residency program director (in fact he was MY residency program director), and he's written before for tl;dr pharmacy here and here. You will likely be seeing more from Dev on the site in the coming months, so get nice and acquainted and give him a warm tl;dr welcome!
 

Drug

Meropenem-Vaborbactam

Indication

FDA approved indications:

  • Complicated urinary tract infections (including pyelonephritis, caused by the following organisms:
    • Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species
  • More specifically indicated for multi-drug resistant infections caused by gram negative bacteria

How it Works

Vabomere (meropenem and vaborbactam) is a combination of meropenem, a carbapenem antibiotic, and vaborbactam, a beta-lactamase inhibitor.

You can consider it a more recent example of the "beta-lactam + beta-lactamase inhibitor" combo antibiotics such as

  • Zosyn (pipercillin + tazobactam)
  • Unasyn (ampicillin + sulbactam)
  • Augmentin (amoxicillin + clavulanate)

The meropenem component of Vabomere is a "hot off the press" carbapenem antibiotic approved in 1996 (yes, before some of you were born).

The bactericidal activity of meropenem results from inhibition of cell wall synthesis via binding to certain penicillin binding protein (PBP) targets.

If bacteria cannot build or maintain a cell wall, they will quickly die (which is why pretty much all beta-lactams are thought of as bactericidal). 

Bacteria generally aren't thrilled about some punk antibiotic coming in and busting up their cell walls...so they start developing mechanisms of resistance (I'll talk more about these in a second). 

One of those mechanisms of resistance is to make an enzyme that destroys the antibiotic (in this case, a beta-lactamase). By itself, meropenem is stable to hydrolysis by most beta-lactamases produced by gram negative and gram positive bacteria.

But (and this sounds obvious now that I'm typing it), meropenem is NOT stable against carbapenem hydrolyzing beta-lactamases. 

 This is what vaborbactam looks like in my mind ( Image )

This is what vaborbactam looks like in my mind (Image)

This is where vaborbactam comes to the rescue!

Vaborbactam is a novel beta-lactamase inhibitor that inhibits both class A and class C beta-lactamases (a.k.a. serine beta-lactamases).

For testing purposes, I would remember that this includes K. pneumoniae carbapenemases (KPC).

(So Vabomere is a treatment option for KPC).

Similar to other beta-lactamase inhibitors, vaborbactam itself has no antibacterial activity, nor does it decrease the activity of meropenem against meropenem-susceptible organisms.

It just helps to protect the antibiotic (meropenem) from getting chewed up by the beta-lactamases produced by bacteria. 

Vabomere Spectrum of Activity

Consider the spectrum of activity for Vabomere as similar to regular meropenem but with potential activity against some meropenem-resistant organisms.

  • Gram positive activity - solid (exceptions: MRSA, VRE)
  • Gram negative activity - excellent (including pseudomonas spp)
  • Anaerobic activity - solid
  • Atypical activity - none

Let me circle back and talk about that bacterial resistance I mentioned earlier. 

Briefly...the mechanisms of beta-lactam resistance include

  • The production of various types of beta-lactamases
  • Modifications of PBP targets
  • Up-regulation of efflux pumps
  • Loss of outer membrane porin

Vaborbactam has demonstrated activity against enterobacteriaceae in the presence of various beta-lactamases, including:

  • KPC
  • SME
  • TEM
  • CTX-M
  • CMY
  • ACT

Unless you go on to be a specialist, you can probably ignore most of the acronyms above...but I would highlight KPC (see, I even bolded it for you).

The most common carbapenamase producing enzyme in the United States is Klebsiella pneumoniae carbapenemase, or KPC. Studies have demonstrated that the addition of vaborbactam at 8 mg/L to meropenem resulted in a greater than 16-fold reduction in MICs for KPC-producing E. coli, K. pneumoniae and Enterobacter spp. isolates.

Of note...

Vabomere is NOT active against bacteria that produce metallo-beta lactamases (i.e. NMD-1) OR oxacillinases (i.e. OXA-48) with carbapenemase activity.

Furthermore, Vabomere may not have activity against bacteria that exhibit resistance to meropenem via a non-beta lactamase mediated mechanism such as efflux pumps.

This is an important caveat. What it means is that adding vaborbactam will not necessarily enhance meropenem's activity against bacteria that have developed resistance to meropenem via non-beta lactamase mediated mechanisms.

Notable Adverse Effects

As with other beta-lactam antibiotics, due to their low likelihood of affecting human cells, the adverse effect profile of Vabomere is relatively benign.

Nonetheless, here are adverse effects worth taking note of...

  • Seizure potential & other CNS experiences
    • Have been reported with meropenem (so naturally you've got to watch out for them in a compound with meropenem in it)
    • Occurred more commonly in patients with underlying CNS disorders (i.e. epilepsy)
  • Thrombocytopenia
    • Has been reported (rare)
    • Clinically significant bleeding has not been reported

Vabomere's Drug Interaction with Valproic Acid

The concomitant use of Vabomere and valproic acid or divalproex (Depakote) is not recommended. There are numerous reports showing that meropenem can significantly decrease valproic acid levels (which lowers the seizure threshold and increases seizure risk).

This is bad news considering that meropenem already has an underlying risk of causing seizures, and most (but not all) patients taking valproic acid are taking it because of a seizure disorder.  

In my observation increasing the dose of valproic acid is not sufficient to overcome this interaction. For patients on valproic acid or divalproex who need concurrent meropenem or meropenem-vaborbactam, it's important to recommend supplemental anticonvulsant therapy.

Current Place in Therapy

The emergence of multi-drug resistant gram negative bacteria has created a huge challenge in the treatment infections both in and out of the hospital setting.

As you probably know, we have a relatively limited armamentarium of antibiotics against these gram negative bacteria that are rapidly becoming resistant to even our last-line of antibiotics.

Vabomere is one of the latest beta-lactam/beta-lactamase inhibitor combinations we have for the treatment of these types of multi-drug resistant gram negative organisms.

Although only FDA approved for complicated urinary tract infections (cUTI), it will likely be used off-label for nosocomial pneumonia or bacteremia caused by MDR gram negative organisms.

The only caveat with using Vabomere for these off-label indications is that we don't have data on how to dose it (although there's currently ongoing trial in patients with hospital and ventilator acquired pneumonia).

The only dosing guidance we have currently is from the package insert for the treatment of UTIs:

4 gm IV q8h (2 gm of meropenem and 2 gm of vaborbactam), administered as an intravenous infusion over 3 hours.

There are also some dose adjustments for renal insufficiency:

  • CrCl 30-49 mL/min: 2 gm IV q8h
  • CrCl 15-29 mL/min: 2 gm IV q12h
  • Less than 15 mL/min: 1 gm IV q12h

All in all, the key points for Vabomere's potential place in therapy are:

  • It's a great treatment option for infections due to carbapenem resistant enterobacteriaceae (CRE), specifically KPC producing carbapenamases
    • Caveat: awaiting actual data for other infections beyond UTIs but based on how we use meropenem many clinicians can infer that the drug will likely be effective for bacteremias, pneumonia, etc.
  • It's NOT NECESSARILY an option for multi-drug resistant (MDR) Pseudomonas infections that are resistant to meropenem...again, since this may not solely be a beta-lactamase mediated resistance mechanism. Would need confirmed microbiology data prior to prescribing for this indication.
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